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Penetration of doripenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers.

ABSTRACT: 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 · 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.

SUBMITTER: Burian B

PROVIDER: S-EPMC3256072 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Penetration of doripenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers.

Burian Bernhard B Zeitlinger Markus M Donath Oliver O Reznicek Gottfried G Sauermann Robert R

Antimicrobial agents and chemotherapy 20111114 1

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 ...[more]

PMID: 22083466

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Project description:Key pointsMuscle infiltration with adipose tissue (IMAT) is common and associated with loss of skeletal muscle strength and physical function across a diverse set of pathologies. Whether the association between IMAT and muscle weakness is causative or simply correlative remains an open question that needs to be addressed to effectively guide muscle strengthening interventions in people with increased IMAT. In the present studies, we demonstrate that IMAT deposition causes decreased muscle strength using mouse models. These findings indicate IMAT is a novel therapeutic target for muscle dysfunction.AbstractIntramuscular adipose tissue (IMAT) is associated with deficits in strength and physical function across a wide array of conditions, from injury to ageing to metabolic disease. Due to the diverse aetiologies of the primary disorders involving IMAT and the strength of the associations, it has long been proposed that IMAT directly contributes to this muscle dysfunction. However, infiltration of IMAT and reduced strength could both be driven by muscle disuse, injury and systemic disease, making IMAT simply an 'innocent bystander.' Here, we utilize novel mouse models to evaluate the direct effect of IMAT on muscle contraction. First, we utilize intramuscular glycerol injection in wild-type mice to evaluate IMAT in the absence of systemic disease. In this model we find that, in isolation from the neuromuscular and circulatory systems, there remains a muscle-intrinsic association between increased IMAT volume and decreased contractile tension (r2 > 0.5, P < 0.01) that cannot be explained by reduction in contractile material. Second, we utilize a lipodystrophic mouse model which cannot generate adipocytes to 'rescue' the deficits. We demonstrate that without IMAT infiltration, glycerol treatment does not reduce contractile force (P > 0.8). Taken together, this indicates that IMAT is not an inert feature of muscle pathology but rather has a direct impact on muscle contraction. This finding suggests that novel strategies targeting IMAT may improve muscle strength and function in a number of populations.

Project description:Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients (n = 10) with DFI were compared with those in healthy volunteers (n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (Cmax), 55.2 ?g/ml (range, 40.9 to 169.3 ?g/ml); half-life (t1/2), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC0-8), 191.6 ?g · h/ml (range, 147.1 to 286.6 ?g · h/ml). The median AUC for tissue (AUCtissue; where AUCtissue was the AUC0-8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (fAUCplasma) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 ?g/ml (the Pseudomonas aeruginosa susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: Cmax, 14.2 ?g/ml (range, 7.6 to 64.2 ?g/ml); t1/2, 2.0 h (range, 0.7 to 2.4 h); and AUC0-8, 27.1 ?g · h/ml (range, 15.0 to 70.0 ?g · h/ml). The AUCtissue (where AUCtissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/fAUCplasma for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: Cmax, 91.5 ?g/ml (range, 65.7 to 110.7 ?g/ml); t1/2, 1.9 h (range, 1.6 to 2.1 h); and AUC0-8, 191.3 ?g · h/ml (range, 118.1 to 274.3 ?g · h/ml). The median AUCtissue/fAUCplasma was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 ?g/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: Cmax, 17.5 ?g/ml (range, 15.4 to 27.3 ?g/ml); t1/2, 0.7 h (range, 0.6 to 0.8 h); and AUC0-8, 22.2 ?g · h/ml (range, 19.2 to 36.4 ?g · h/ml). The AUCtissue/fAUCplasma for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.).

Dataset Information

Penetration of doripenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers.

Publications

Penetration of doripenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers.

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