The objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) treatment and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 h. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations. A population PK model of SCT and plasma data was developed using NONMEM. Time above clinical breakpoint MIC for (8 mg/liter) was predicted for each patient. The following targets were evaluated: time for which the free (unbound) concentration is maintained above the MIC of at least 40% (40%T>MIC), 100% T>MIC, and 100% T>4×MIC. For all dosing regimens simulated in both plasma and SCT, 40% T>MIC was attained. However, prolonged meropenem infusion would be needed for 100% T>MIC and 100% T>4×MIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine clearance (eCL). Simulations showed that in patients with increased eCL, dose increment or continuous infusion may be needed to obtain therapeutic meropenem concentrations. In conclusion, our results show that using traditional targets of 40% T>MIC for standard meropenem dosing of 1 g intravenously every 8 h is likely to provide sufficient meropenem concentration to treat the problematic pathogen for patients receiving ECMO treatment. However, for patients with an increased eCL, or if more aggressive targets, like 100% T>MIC or 100% T>4×MIC, are adopted, incremental dosing or continuous infusion may be needed.

Background and purposeThe incidence of orthopedic methicillin-resistant Staphylococcus aureus (MRSA) infections is increasing. Vancomycin may therefore play an increasingly important role in orthopedic perioperative antimicrobial prophylaxis. Studies investigating perioperative bone and soft tissue concentrations of vancomycin are sparse and challenged by a lack of appropriate methods. We assessed single-dose plasma, subcutaneous adipose tissue (SCT) and bone concentrations of vancomycin using microdialysis in male patients undergoing total knee replacement.Methods1,000 mg of vancomycin was administered postoperatively intravenously over 100 minutes to 10 male patients undergoing primary total knee replacement. Vancomycin concentrations in plasma, SCT, cancellous, and cortical bone were measured over the following 8 hours. Microdialysis was applied for sampling in solid tissues.ResultsFor all solid tissues, tissue penetration of vancomycin was significantly impaired. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 2 mg/L was 3, 36, 27, and 110 min for plasma, SCT, cancellous, and cortical bone, respectively. As opposed to the other compartments, a mean MIC of 4 mg/L could not be reached in cortical bone. The area under the concentration-time curve from 0 to the last measured value and peak drug concentrations (Cmax) for SCT, cancellous, and cortical bone was lower than that of free plasma. The time to Cmax was higher for all tissues compared with free plasma.InterpretationPostoperative penetration of vancomycin to bone and SCT was impaired and delayed in male patients undergoing total knee replacement surgery. Adequate perioperative vancomycin concentrations may not be reached using standard prophylactic dosage.

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.

These findings support the general clinical perception that fast diagnosis and early initiation of antibiotics before the development of implant-associated cavities is important in nonsurgical management of acute osteomyelitis.

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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.

Background and purpose - Vancomycin may be an important drug for intravenous perioperative antimicrobial prophylaxis in spine surgery. We assessed single-dose vancomycin intervertebral disc, vertebral cancellous bone, and subcutaneous adipose tissue concentrations using microdialysis in a pig model. Material and methods - 8 female pigs received 1,000 mg of vancomycin intravenously as a single dose over 100 minutes. Microdialysis probes were placed in the C3-C4 intervertebral disc, C3 vertebral cancellous bone, and subcutaneous adipose tissue, and vancomycin concentrations were obtained over 8 hours. Venous blood samples were obtained as reference. Results - Ranging from 0.24 to 0.60, vancomycin tissue penetration, expressed as the ratio of tissue to plasma area under the concentration-time curve from 0 to the last measured value, was incomplete for all compartments. The lowest penetration was found in the intervertebral disc. The time to a mean clinically relevant minimal inhibitory concentration (MIC) of 4 µg/mL was 3, 17, 25, and 156 min for plasma, subcutaneous adipose tissue, vertebral cancellous bone, and the intervertebral disc, respectively. In contrast to the other compartments, a mean MIC of 8 µg/mL was not reached in the intervertebral disc. An approximately 3-times longer elimination rate was observed in the intervertebral disc in comparison with all the other compartments (p < 0.001), and the time to peak drug concentration was higher for all tissues compared with plasma Interpretation - Preoperative administration of 1,000 mg of vancomycin may provide adequate vancomycin tissue concentrations with a considerable delay, though tissue penetration was incomplete. However, in order also to achieve adequate intervertebral disc concentrations in all individuals and accommodating a potentially higher MIC target, supplemental application of vancomycin may be necessary.