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 Pseudomonas aeruginosa (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% f T>MIC), 100% f T>MIC, and 100% f T>4×MIC. For all dosing regimens simulated in both plasma and SCT, 40% f T>MIC was attained. However, prolonged meropenem infusion would be needed for 100% f T>MIC and 100% f T>4×MIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine clearance (eCL _Cr ). Simulations showed that in patients with increased eCL _Cr , dose increment or continuous infusion may be needed to obtain therapeutic meropenem concentrations. In conclusion, our results show that using traditional targets of 40% f 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 P. aeruginosa for patients receiving ECMO treatment. However, for patients with an increased eCL _Cr , or if more aggressive targets, like 100% f T>MIC or 100% f T>4×MIC, are adopted, incremental dosing or continuous infusion may be needed.

Background and purpose - The 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. Methods - 1,000 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. Results - For 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. Interpretation - Postoperative 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.

Pigs are favorable experimental animals for infectious diseases in humans. However, implant‐associated osteomyelitis (IAO) models in pigs have only been evaluated using high‐inoculum infection (>10⁸ CFU) models in 1975 and 1993. Therefore, the aim of this paper was to present a new low inoculum porcine model of human IAO based on 42 experimental pigs. The model was created by drilling an implant cavity in the tibial bone followed by insertion of a small steel implant and simultaneous inoculation of Staphylococcus aureus bacteria (n = 32) or saline (n = 10). The infected pigs were either inoculated with 10⁴ CFU (n = 26) or 10² and 10³ CFU (n = 6). All animals were euthanized 5 days after insertion of implants. Pigs receiving the high‐inoculum infections showed a significantly higher volume of bone lesion, number of neutrophils around the implant, concentrations of acute phase proteins in serum, and enlargement of regional lymph nodes. A positive correlation was present between a high number of surrounding neutrophils and high values of all other parameters. Furthermore, a threshold of 40 neutrophils per 10 high power fields for the histopathological diagnosis of high grade IAO was defined. In conclusion: This paper describes a novel low‐inoculum S. aureus porcine model of IAO which was demonstrated to be reliable, reproducible and discriminative to human IAO, and represents a requested and valuable tool in orthopedic research. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2211–2221, 2017.

The prolonged antibiotic therapy that is often needed for successful management of osteomyelitis may be related to incomplete penetration of antibiotics into the target site. The objective of this study was to assess the effects of implant-associated osteomyelitis on cefuroxime penetration into bone. Implant-associated osteomyelitis using a Staphylococcus aureus strain was induced in the right tibia in ten pigs. After five days and following administration of 1500 mg of cefuroxime, measurements of cefuroxime were obtained using microdialysis for eight hours in the implant-related bone cavity, in the adjacent infected cancellous bone and infected subcutaneous tissue, and in healthy cancellous bone and subcutaneous tissue in the contralateral leg. Measurements of the corresponding free plasma concentrations were also obtained. The extent of the infection was assessed by postmortem computed tomography (CT) scans and cultures of blood, swabs, and bone specimens. Bone destruction was found in the implant cavities. No structural bone changes in the adjacent infected cancellous bone were visible on CT scans. S. aureus was grown on culture of specimens from all implant cavities and from eight of ten swabs and seven of ten bone samples from the infected bone. The areas under the concentration-time curves for the different tissues differed significantly, with the lowest area under the curve found in the implant cavity (analysis of variance; p < 0.001). Although not as notable as for the implant cavity, cefuroxime penetration into infected cancellous bone was incomplete but comparable with that in healthy bone. Despite poorer tissue penetration, slightly increased time with concentrations above the minimal inhibitory concentration (MIC) was achieved in the implant cavity up to MICs of 2 mg/L compared with the other tissues, but the time was shorter for higher MICs. Cefuroxime penetration into infected cancellous bone was incomplete but comparable with that in healthy bone. The destructive bone processes associated with acute osteomyelitis reduced cefuroxime penetration further. 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.

Piperacillin is a β-lactam antimicrobial frequently used in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT). However, data regarding piperacillin tissue concentrations in this patient population are limited. A prospective observational study was conducted of free piperacillin concentrations during a single 8-h dosing interval in plasma (8 samples) and subcutaneous tissue (SCT) (13 samples), in 10 patients treated with CRRT following piperacillin 4 g given every 8 h as intermittent administration over 3 min. A population pharmacokinetic model was developed using NONMEM 7.4.3, to simulate alternative administration modes and dosing regimens. SCT concentrations were obtained using microdialysis. Piperacillin concentrations were compared to the clinical breakpoint minimum inhibitory concentration (MIC) for Pseudomonas aeruginosa (16 mg/l), with evaluation of the following pharmacokinetic/pharmacodynamics targets: 50% fT > 1 × MIC, 100% fT > 1 × MIC, and 100% fT > 4 × MIC. SCT concentrations were generally lower than plasma concentrations. For the target of 50% free time (fT) > 1 × MIC and 100% fT > 1 × MIC, piperacillin 4 g every 8 h resulted in probability of target attainment (PTA) >90% in both plasma and SCT. PTA > 90% for the target of 100% fT > 4 × MIC was only achieved for continuous infusion. Piperacillin 4 g every 8 h is likely to provide sufficient exposure in both plasma and SCT to treat P.aeruginosa infections in critically ill patients on CRRT, given that targets of 50% fT > 1 × MIC or 100% fT > 1 × MIC are adequate. However, if a more aggressive target of 100% fT > 4 × MIC is adopted, continuous infusion is needed.