Pharmacokinetics of double-dose cefuroxime in porcine intervertebral disc and vertebral cancellous bone—a randomized microdialysis study

Hanberg, Pelle; Bue, Mats; Jørgensen, Andrea René; Thomassen, Maja; Öbrink-Hansen, Kristina; Søballé, Kjeld; Stilling, Maiken

doi:10.1016/j.spinee.2020.03.006

Cited by 11 publications

(14 citation statements)

References 24 publications

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“…However, this approach suffers from important methodological limitations because sampling in clinical studies is limited to the time of surgery, free extracellular concentrations cannot be measured selectively, and drug concentrations are given by mass rather than volume (Landersdorfer et al 2009 ). Microdialysis, on the other hand, allows for simultaneous and serial sampling of the free and active fraction of drugs in the interstitial space from multiple compartments, both peri- and postoperatively (Tottrup et al 2016 , Hanberg et al 2020a ). These features are desirable, as the majority of infections occur in the interstitial space.…”

Section: Discussionmentioning

confidence: 99%

Effects of tourniquet inflation on peri- and postoperative cefuroxime concentrations in bone and tissue

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Effects of tourniquet inflation on peri- and postoperative cefuroxime concentrations in bone and tissue

et al. 2021

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“…Microdialysis is a catheter-based method for continuous sampling of the free unbound and active fraction of antibiotics in the interstitial space of the tissue of interest [ 43 , 44 , 45 ]. A semipermeable membrane at the tip of the catheter allows solutes to diffuse along the concentration gradient, but without achieving equilibrium, as the microdialysis catheter is constantly perfused.…”

Section: Methodsmentioning

confidence: 99%

“…Microdialysis is a catheter-based method for continuous sampling of the free unbound and active fraction of antibiotics in the interstitial space of the tissue of interest [43][44][45].…”

Section: Microdialysismentioning

confidence: 99%

High Cefuroxime Concentrations and Long Elimination in an Orthopaedic Surgical Deadspace—A Microdialysis Porcine Study

et al. 2022

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Deadspace is the tissue and bony defect in a surgical wound after closure. This space is presumably poorly perfused favouring bacterial proliferation and biofilm formation. In arthroplasty surgery, an obligate deadspace surrounding the prosthesis is introduced and deadspace management, in combination with obtaining therapeutic prophylactic antibiotic concentrations, is important for limiting the risk of acquiring a periprosthetic joint infection (PJI). This study aimed to investigate cefuroxime distribution to an orthopaedic surgical deadspace in comparison with plasma and bone concentrations during two dosing intervals (8 h × 2). In a setup imitating shoulder arthroplasty surgery, but without insertion of a prosthesis, microdialysis catheters were placed for cefuroxime sampling in a deadspace in the glenohumeral joint and in cancellous bone of the scapular neck in eighteen pigs. Blood samples were collected as a reference. Cefuroxime was administered according to weight (20 mg/kg). The primary endpoint was time above the cefuroxime minimal inhibitory concentration of the free fraction of cefuroxime for Staphylococcus aureus (fT > MIC (4 μg/mL)). During the two dosing intervals, mean fT > MIC (4 μg/mL) was significantly longer in deadspace (605 min) compared with plasma (284 min) and bone (334 min). For deadspace, the mean time to reach 4 μg/mL was prolonged from the first dosing interval (8 min) to the second dosing interval (21 min), while the peak drug concentration was lower and half-life was longer in the second dosing interval. In conclusion, weight-adjusted cefuroxime fT > MIC (4 μg/mL) and elimination from the deadspace was longer in comparison to plasma and bone. Our results suggest a deadspace consolidation and a longer diffusions distance, resulting in a low cefuroxime turn-over. Based on theoretical targets, cefuroxime appears to be an appropriate prophylactic drug for the prevention of PJI.

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“…Since animal models of spondylodiscitis are work-intensive and only allow low throughput and read-outs, we aimed at establishing a porcine ex vivo model to assess the initial interaction between S. aureus and IVD cells in their native environment. Porcine models are more frequently used as preclinical models in infectious diseases, since their anatomical, physiological and immunological response properties are close to those of humans (10)(11)(12). Furthermore, pigs, as well as humans, are frequently colonized with Staphylococcus spp.…”

Section: Introductionmentioning

confidence: 99%

Intervertebral disc cell chondroptosis elicits neutrophil response inStaphylococcus aureusspondylodiscitis

Schweizer

Andreoni

Acevedo

et al. 2022

Preprint

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Objective: To understand the pathophysiology of spondylodiscitis due to Staphylococcus aureus, an emerging infectious disease of the intervertebral disc (IVD) and vertebral body with a high complication rate, by combining clinical insights and experimental approaches. Methods: Clinical data and histological material of nine patients suffering from S. aureus spondylodiscitis were retrospectively collected at a single center. To mirror the clinical findings experimentally, we developed a novel porcine ex vivo model mimicking acute S. aureus spondylodiscitis and assessed the interaction between S. aureus and IVD cells within their native environment. In addition, the inflammatory features underlying this interaction were assessed in primary human IVD cells. Finally, mirroring the clinical findings, we assessed primary human neutrophils for their ability to respond to secreted inflammatory modulators of IVD cells upon S. aureus challenge. Results: Acute S. aureus spondylodiscitis in patients was characterized by tissue necrosis and neutrophil infiltration. Additionally, the presence of empty IVD cells lacunae was observed. This was mirrored in the ex vivo porcine model, where S. aureus induced extensive IVD cell death, leading to empty lacunae. Concomitant engagement of the apoptotic and pyroptotic cell death pathways was observed in primary human IVD cells, resulting in cytokine release. Among the released cytokines, functionally intact neutrophil-priming as well as broad pro- and anti-inflammatory cytokines known for their involvement in IVD degeneration were found. Conclusions: In patients as well as ex vivo in a novel porcine model, S. aureus spondylodiscitis infection caused IVD cell death, resulting in empty lacunae, which was accompanied by release of inflammation markers and recruitment of neutrophils. These findings offer valuable insights into the important role of inflammatory IVD cell death during the onset of spondylodiscitis and potential future therapeutic approaches.

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Pharmacokinetics of double-dose cefuroxime in porcine intervertebral disc and vertebral cancellous bone—a randomized microdialysis study

Cited by 11 publications

References 24 publications

Effects of tourniquet inflation on peri- and postoperative cefuroxime concentrations in bone and tissue

Effects of tourniquet inflation on peri- and postoperative cefuroxime concentrations in bone and tissue

High Cefuroxime Concentrations and Long Elimination in an Orthopaedic Surgical Deadspace—A Microdialysis Porcine Study

Intervertebral disc cell chondroptosis elicits neutrophil response inStaphylococcus aureusspondylodiscitis

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