AAPS-FDA workshop white paper: Microdialysis principles, application, and regulatory perspectives report from the Joint AAPS-FDA Workshop, November 4–5, 2005, Nashville, TN

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.

Section: Discussionmentioning

confidence: 99%

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

Tøttrup

Hardlei

Bendtsen

et al. 2014

“…The principles of microdialysis have been described in detail previously (3,14,15,17). In brief, microdialysis is based on the continuous sampling of the unbound (i.e., microbiologically active) fraction of analytes from the interstitial space that diffuse through the semipermeable membrane at the tip of the microdialysis probe.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Microdialysis Study of the Penetration of Daptomycin into Soft Tissues in Diabetic versus Healthy Volunteers

Kim

Suecof

Sutherland

et al. 2008

Daptomycin is approved for the treatment of complicated skin and soft tissue infections, including diabetic wounds of the lower extremities, at a dose of 4 mg/kg of body weight once daily. For such localized tissue infections, drug concentrations in the interstitial space are an important determinant of successful therapy. In the diabetic population, peripheral arterial disease may limit antibiotic penetration into the target tissue. The objective of this study was to describe and compare the pharmacokinetic profiles of daptomycin in the interstitial fluid of soft tissues in diabetic and healthy volunteers by using in vivo microdialysis. Twelve subjects (six diabetic and six healthy) received a single 4-mg/kg dose of daptomycin intravenously. Samples of plasma and tissue were simultaneously collected over 24 h. Diabetic and healthy groups were matched in mean age (؎10 years), gender ratio, mean weight (؎10 kg), and creatinine clearance rate (؎20 ml/min/1.73 m 2 ). Pharmacokinetic parameters for plasma were similar between groups (P > 0.05). The mean peak drug concentrations ؎ standard deviations in tissue were 4.3 ؎ 3.3 g/ml and 3.8 ؎ 1.4 g/ml for diabetic and healthy subjects, respectively. The degree of tissue penetration, defined as the ratio of the area under the free drug concentration-time curve for tissue to that for plasma, was 0.93 ؎ 0.61 for diabetic subjects and 0.74 ؎ 0.09 for healthy subjects (P ‫؍‬ 0.46). Daptomycin at 4 mg/kg penetrated well into the soft tissue, reaching concentrations approximately 70 to 90% of those of the free drug in plasma. Moreover, these free, bioactive concentrations in tissue exceeded the MICs for staphylococci and streptococci over the 24-h dosing interval.Wound infections of the lower extremities frequently affect the diabetic population and are a significant cause of morbidity, hospitalization, and amputation (12). Gram-positive organisms, particularly Staphylococcus aureus, are the primary causative pathogens in these complicated skin infections. As the extent of antibiotic resistance has grown, the prevalence of methicillin-resistant S. aureus (MRSA) in skin and soft tissue infections (SSTI) has risen alarmingly, resulting in reports of worse outcomes for infections caused by MRSA than for infections caused by other bacteria (20).Anti-MRSA agents like daptomycin are increasingly in demand, particularly in light of recent queries regarding vancomycin's efficacy and continued utility (7). Daptomycin is approved for the treatment of complicated SSTI, including diabetic wound infections, at an intravenous dose of 4 mg/kg of body weight once daily (1, 13). While the pharmacokinetic profile of daptomycin in plasma has been reported previously, for localized tissue infections, drug concentrations in the interstitial space rather than those in plasma determine clinical outcomes. Moreover, diabetic patients also typically suffer from peripheral arterial disease (PAD), which may further limit antibiotic concentrations in infected tissues, as was shown previously for vancomyci...

“…Due to mandatory correction for RR in pharmacokinetic studies, a magnification of the variations associated with the preanalytical sample handling and chemical assay is inherent to the MD approach. These variations will increase exponentially with decreasing recovery (17). Consequently, MD studies should always be interpreted with this possible limitation in mind.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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

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...