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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.).

Project description:BACKGROUND: Recovering high quality intact RNA from post-mortem tissue is of major concern for gene expression studies in animals and humans. Since the availability of post-mortem tissue is often associated with substantial delay, it is important that we understand the temporal variation in the stability of total RNA and of individual gene transcripts so as to be able to appropriately interpret the data generated from such studies. Hence, the objective of this experiment was to qualitatively and quantitatively assess the integrity of total and messenger RNA extracted from bovine skeletal muscle, subcutaneous adipose tissue and liver stored at 4 degrees C at a range of time points up to 22 days post-mortem. These conditions were designed to mimic the environment prevailing during the transport of beef from the abattoir to retail outlets. RESULTS: The 28S and 18S rRNA molecules of total RNA were intact for up to 24 h post-mortem in liver and adipose tissues and up to 8 days post-mortem in skeletal muscle. The mRNA of housekeeping genes (GAPDH and ACTB) and two diet-related genes (RBP5 and SCD) were detectable up to 22 days post-mortem in skeletal muscle. While the mRNA stability of the two housekeeping genes was different in skeletal muscle and liver, they were similar to each other in adipose tissue. After 22 days post-mortem, the relative abundance of RBP5 gene was increased in skeletal muscle and in adipose tissue and decreased in liver. During this period, the relative abundance of SCD gene also increased in skeletal muscle whereas it decreased in both adipose tissue and liver. CONCLUSION: Stability of RNA in three tissues (skeletal muscle, subcutaneous adipose tissue and liver) subjected to long-term post-mortem storage at refrigeration temperature indicated that skeletal muscle can be a suitable tissue for recovering biologically useful RNA for gene expression studies even if the tissue is subjected to post-mortem storage for weeks, whereas adipose tissue and liver should be processed within 24 hours post-mortem.

Project description:BackgroundPersistent loss of skeletal muscle mass and function as well as altered fat metabolism are frequently observed in severe sepsis survivors. Studies examining sepsis-associated tissue dysfunction from the perspective of the tissue microenvironment are scarce. In this study, we comprehensively assessed transcriptional changes in muscle and fat at single-cell resolution following experimental sepsis induction.MethodsSkeletal muscle and visceral white adipose tissue from control mice or mice 1 day or 1 month following faecal slurry-induced sepsis were used. Single cells were mechanically and enzymatically prepared from whole tissue, and viable cells were further isolated by fluorescence activated cell sorting. Droplet-based single-cell RNA-sequencing (scRNA-seq; 10× Genomics) was used to generate single-cell gene expression profiles of thousands of muscle and fat-resident cells. Bioinformatics analyses were performed to identify and compare individual cell populations in both tissues.ResultsIn skeletal muscle, scRNA-seq analysis classified 1438 single cells into myocytes, endothelial cells, fibroblasts, mesenchymal stem cells, macrophages, neutrophils, T-cells, B-cells, and dendritic cells. In adipose tissue, scRNA-seq analysis classified 2281 single cells into adipose stem cells, preadipocytes, endothelial cells, fibroblasts, macrophages, dendritic cells, B-cells, T-cells, NK cells, and gamma delta T-cells. One day post-sepsis, the proportion of most non-immune cell populations was decreased, while immune cell populations, particularly neutrophils and macrophages, were highly enriched. Proportional changes of endothelial cells, neutrophils, and macrophages were validated using faecal slurry and cecal ligation and puncture models. At 1 month post-sepsis, we observed persistent enrichment/depletion of cell populations and further uncovered a cell-type and tissue-specific ability to return to a baseline transcriptomic state. Differential gene expression analyses revealed key genes and pathways altered in post-sepsis muscle and fat and highlighted the engagement of infection/inflammation and tissue damage signalling. Finally, regulator analysis identified gonadotropin-releasing hormone and Bay 11-7082 as targets/compounds that we show can reduce sepsis-associated loss of lean or fat mass.ConclusionsThese data demonstrate persistent post-sepsis muscle and adipose tissue disruption at the single-cell level and highlight opportunities to combat long-term post-sepsis tissue wasting using bioinformatics-guided therapeutic interventions.

Dataset Information

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

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

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