Quantification and prediction of skin pharmacokinetics of amoxicillin and cefuroxime

Shukla, Chinmay; Patel, Vishal; Juluru, Ravi; Stagni, Grazia

doi:10.1002/bdd.658

Cited by 24 publications

(12 citation statements)

References 26 publications

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“…Accordingly, MD seems to be a valuable tool for assessing tissue distribution of cefuroxime in studies lasting several hours and with possible physiological changes in temperature. This is in agreement with the findings in previous studies (7,27,28).…”

Section: Discussionsupporting

confidence: 94%

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

Tøttrup

Hardlei

Bendtsen

et al. 2014

Antimicrob Agents Chemother

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f Traditionally, the pharmacokinetics of antimicrobials in bone have been investigated using bone biopsy specimens, but this approach suffers from considerable methodological limitations. Consequently, new methods are needed. The objectives of this study were to assess the feasibility of microdialysis (MD) for measuring cefuroxime in bone and to obtain pharmacokinetic profiles for the same drug in porcine cortical and cancellous bone. The measurements were conducted in bone wax sealed and unsealed drill holes in cortical bone and in drill holes in cancellous bone and in subcutaneous tissue. As a reference, the free and total plasma concentrations were also measured. The animals received a bolus of 1,500 mg cefuroxime over 30 min. No significant differences were found between the key pharmacokinetic parameters for sealed and unsealed drill holes in cortical bone. The mean ؎ standard error of the mean area under the concentration-time curve (AUC) values from 0 to 5 h were 6,013 ؎ 1,339, 3,222 ؎ 1086, 2,232 ؎ 635, and 952 ؎ 290 min · g/ml for free plasma, subcutaneous tissue, cancellous bone, and cortical bone, respectively (P < 0.01, analysis of variance). The AUC for cortical bone was also significantly different from that for cancellous bone (P ‫؍‬ 0.04). This heterogeneous tissue distribution was also reflected in other key pharmacokinetic parameters. This study validates MD as a suitable method for measuring cefuroxime in bone. Cefuroxime penetration was impaired for all tissues, and bone may not be considered one distinct compartment.

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Section: Discussionsupporting

confidence: 94%

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

Tøttrup

Hardlei

Bendtsen

et al. 2014

Antimicrob Agents Chemother

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“…A thorough description of MD can be found elsewhere . In brief, MD is a probe‐based method enabling continuous sampling of water‐soluble molecules from the tissue of interest . Owing to the continuous perfusion and the semipermeable membrane at the tip of the probe, a non‐equilibrium diffusion of molecules following the concentration gradient will occur.…”

Section: Methodsmentioning

confidence: 99%

Single‐dose bone pharmacokinetics of vancomycin in a porcine implant‐associated osteomyelitis model

Bue

Hanberg

Koch

et al. 2017

Journal Orthopaedic Research

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The increasing incidence of orthopaedic methicillin-resistant Staphylococcus aureus (MRSA) infections represents a significant therapeutic challenge. Being effective against MRSA, the role of vancomycin may become more important in the orthopaedic setting in the years to come. Nonetheless, vancomycin bone and soft tissue penetration during infection remains unclear. In eight pigs, implant-associated osteomyelitis was induced on day 0, using a Staphylococcus aureus strain. Following administration of 1,000 mg of vancomycin on day 5, vancomycin concentrations were obtained with microdialysis for 8 h in the implant bone cavity, in cancellous bone adjacent to the implant cavity, in subcutaneous adipose tissue (SCT) adjacent to the implant cavity, and in healthy cancellous bone and healthy SCT in the contralateral leg. Venous blood samples were also obtained. The extent of infection and inflammation was evaluated by post-mortem computed tomography scans, C-reactive protein serum levels and cultures of blood and swabs. In relation to all the implant cavities, bone destruction was found. Ranging from 0.20 to 0.74, tissue penetration, expressed as the ratio of the area under the concentration-time curve from 0 to the last measured value, was incomplete for all compartments except for healthy SCT. The lowest penetration was found in the implant cavity. In conclusion, Staphylococcus aureus implant-associated osteomyelitis was found to reduce vancomycin bone penetration, especially in the implant cavity. These findings suggest that it may be unsafe to rely solely on vancomycin therapy when treating acute osteomyelitis. Particularly when metaphyseal cavities are present, surgical debridement seems necessary. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1093-1098, 2018.

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“…The principles of MD have been described in detail elsewhere (17)(18)(19). Briefly, MD is a minimally invasive probe-based technique that allows for continuous sampling of small unbound water-soluble molecules in the interstitial spaces of virtually all tissues (10,(20)(21)(22)(23)(24). The diffusion of solutes takes place across a semipermeable membrane at the tip of the probe along the concentration gradient.…”

Section: Methodsmentioning

confidence: 99%

Continuous versus Short-Term Infusion of Cefuroxime: Assessment of Concept Based on Plasma, Subcutaneous Tissue, and Bone Pharmacokinetics in an Animal Model

Tøttrup

Bibby

Hardlei

et al. 2015

Antimicrob Agents Chemother

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The relatively short half-lives of most ␤-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. T he relatively short half-lives of most ␤-lactams suggest that extended infusion (EI) or continuous infusion (CI) of these time-dependent antimicrobials may be favorable compared to short-term infusion (STI). Nevertheless, different meta-analyses evaluating CI versus STI of various time-dependent antimicrobials have failed to convincingly demonstrate improved clinical outcomes on mortality and clinical cure (1-6). It is noteworthy, however, that in the majority of studies included in these metaanalyses, the total daily dose of antimicrobials was lower for patients treated with EI or CI (1, 2, 5). In a subset of randomized controlled trials (RCTs) in which the total daily dose was equivalent in the two intervention arms, the clinical failure rate was lower for patients treated with CI (1).Inferences about the dosing regimens of antimicrobials are commonly based on plasma pharmacokinetics-pharmacodynamics (PK-PD) indices, despite the fact that the majority of bacterial pathogens reside in the interstitial space of solid tissues. However, incomplete and uneven tissue distribution was eventually demonstrated in a number of studies for different combinations of drug and tissue (7-13). As the gap between steady-state plasma concentrations and MICs may be rather limited using CI, incomplete tissue penetration may partly explain why improved clinical outcomes for CI have been difficult to demonstrate, particularly when the total daily dose is reduced.Deep-seated orthopedic infections, like osteomyelitis and implant-associated infections (IAI), are difficult to treat, often requiring extensive surgical debridement and long-lasting antimicrobial therapy (14). In a recent porcine study, we demonstrated substantially impaired bone and subcutaneous tissue (SCT) penetration of cefuroxime (15). The pharmacokinetic profiles suggested that EI or CI of the drug might attain increased time with tissue concentrations above the MIC (TϾMIC) for relevant microorganisms.Ultimately, the dosing regimens of antimicrobials should be based on results of RCTs for a specific combination of drug, bug...

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Quantification and prediction of skin pharmacokinetics of amoxicillin and cefuroxime

Cited by 24 publications

References 26 publications

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

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

Single‐dose bone pharmacokinetics of vancomycin in a porcine implant‐associated osteomyelitis model

Continuous versus Short-Term Infusion of Cefuroxime: Assessment of Concept Based on Plasma, Subcutaneous Tissue, and Bone Pharmacokinetics in an Animal Model

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