Preoperative proximal tibial bone density, bone microarchitecture, and bone turnover are not associated with postoperative tibial component migration in cemented and cementless medial unicompartmental knee replacements: secondary analyses from a randomized controlled trial.

BACKGROUND AND PURPOSE: Cementless arthroplasty fixation relies on early bone ingrowth and may be poor in patients with low proximal tibial bone density or abnormal bone turnover. We aimed first to describe the baseline bone properties in patients undergoing medial unicompartmental knee replacement (UKR), and second to investigate its association with cemented and cementless tibial component migration until 2 years. METHODS: A subset investigation of 2 patient groups from a 3-armed randomized controlled trial was conducted. There were 26 cemented and 25 cementless medial UKRs with twin-pegged femoral components. Volumetric bone mineral density (vBMD) and microstructure of the excised medial tibial plateau were ascertained with µCT. Bone turnover was estimated using dynamic histomorphometry (eroded surface/bone surface = ES/BS, osteoid surface/bone surface = OS/BS, mineralizing surface/bone surface = MS/BS). Tibial component migration in 4 feature points was followed for 2 years with radiostereometry. RESULTS: At the 2-year follow-up, the cementless tibial components migrated 0.38 mm (95% confidence interval [CI] 0.14-0.62) total translation more than the cemented components at the posterior feature point. The greatest migration in the cementless group was subsidence at the posterior feature point of 0.66 mm (CI 0.48-0.84) until 6 weeks, and from 3 months the components were stable. Cemented tibial components subsided very little. Between 1- and 2-year follow-ups, no cementless but 4 cemented tibial components revealed continuous migration. OS/BS was half of the ES/BS. No µCT or histomorphometric parameters showed any clinically relevant correlation with tibial component migration at the posterior feature point for either cemented or cementless UKR at 6 weeks' or 2 years' follow-up after adjustment for age, BMI, and sex. CONCLUSION: Preoperative vBMD, bone turnover, and microstructure were not associated with postoperative tibial component migration of cemented and cementless medial UKR.

Population Pharmacokinetics of Flucloxacillin In Bone and Soft Tissue- Standard Dosing is Not Sufficient to Achieve Therapeutic Concentrations.

PURPOSE: Flucloxacillin is a ß-lactam penicillin commonly used in the treatment of bone and soft tissue infections. In a recent porcine study, we found surprisingly low time for which the free concentration was maintained above the minimal inhibitory concentration (fT>MIC) in bone and soft tissue, following flucloxacillin oral (PO) and intravenous (IV) administration at 1g every 6h (q6h). In addition to plasma, sampling was obtained from subcutaneous tissue, knee joint, cancellous bone and cortical bone, using microdialysis. To identify flucloxacillin dosing regimens that result in theoretically therapeutic concentrations, we developed a population pharmacokinetic (PK) model for the porcine data, and combined it with a human flucloxacillin population PK model for simulations. METHODS: A four-compartment model was developed, and various dosing regimens and modes of administration were simulated. Predicted concentrations were compared to %fT>MIC (0.5 mg/L and 2 mg/L). RESULTS: Continuous infusion (CI) resulted in higher %fT>MIC compared to intermittent administration. For intermittent IV dosing (4, 8 and 12g/24h), fT>MIC (0.5 mg/L) was ≥70% in plasma, and ranged between 42-96% in the sampled tissue in a typical individual. By applying CI, 4g/day was sufficient to achieve ≥98% fT>MIC (0.5 mg/L) in all sampled tissues. For MIC 2 mg/L, ≥50% fT>MIC was only achieved in plasma at CI 8 and 12g/24h and IV 3g q6h. CONCLUSIONS: To reach efficacious flucloxacillin bone and tissue concentrations, dose increment or continuous infusion needs to be considered.

Steady-state concentrations of flucloxacillin in porcine vertebral cancellous bone and intervertebral disc following oral and intravenous administration assessed by microdialysis.

AIMS: Flucloxacillin is a frequently used antibiotic in the treatment of spondylodiscitis. We assessed steady-state concentrations and time above minimal inhibitory concentration (fT > MIC) of flucloxacillin in the intervertebral disc, vertebral cancellous bone, subcutaneous tissue and plasma, after intravenous and oral administration. METHODS: Sixteen pigs were randomized into two groups; Group Peroral (Group PO) and Group Intravenous (Group IV) received 1 g flucloxacillin every 6 h for 24 h orally or intravenously. Microdialysis was used for sampling in the compartments of interest. A flucloxacillin target of 50% fT > MIC was applied for three MIC targets: 0.125, 0.5 and 2.0 µg/mL. RESULTS: Intravenous administration resulted in significantly longer fT > MIC for all targets. Target attainment was only reached for the low target of 0.125 µg/mL in Group IV in vertebral cancellous bone, subcutaneous tissue, and plasma (intervertebral disc 47%). In Group IV, mean fT > MIC values in the investigated compartments were in the range of 47-67% of the dosing interval for 0.125 µg/mL, 20-35% for 0.5 µg/mL, and 0-15% for 2.0 µg/mL. In Group PO, mean fT > MIC values for 0.125 µg/mL were in the range of 1-33%. No pigs reached a concentration of 0.5 µg/mL in any of the investigated compartments in Group PO. CONCLUSION: Administration of 1 g flucloxacillin every 6 h resulted in surprisingly low steady-state fT > MIC after intravenous and oral administration. However, intravenous administration resulted in significantly higher concentrations across compartments compared to oral administration. Sufficient target tissue concentrations for treatment of spondylodiscitis may require a dose increase or alternative dosing regimens.

Effects of rifampicin on moxifloxacin concentrations in porcine cervical spine: a randomized microdialysis study.

BACKGROUND: Pyogenic spondylodiscitis remains a therapeutic challenge, as demonstrated by divergent treatment guidelines. The combination of moxifloxacin and rifampicin may be an attractive treatment option for cases caused by staphylococci; however, previous studies have reported a reduction in plasma concentrations of moxifloxacin when coadministered with rifampicin. The magnitude of this reduction in spinal tissues is not known. OBJECTIVES: To investigate the effect of rifampicin on moxifloxacin tissue concentrations in vertebral cancellous bone, the intervertebral disc and subcutaneous adipose tissue under steady-state conditions using microdialysis in a porcine model. METHODS: Twenty female pigs were randomized into two groups of 10 pigs. Group A received 400 mg of moxifloxacin orally once daily for 3 days preoperatively. Group B received 400 mg of moxifloxacin orally once daily for 3 days preoperatively combined with 450 mg of rifampicin twice daily for 7 days preoperatively. Measurements were obtained from plasma, vertebral cancellous bone, the intervertebral disc and subcutaneous adipose tissue for 24 h. Microdialysis was applied for sampling in solid tissues. RESULTS: Coadministration of moxifloxacin and rifampicin demonstrated a reduction of free moxifloxacin concentrations in spinal tissues. Cmax and AUC0-24 in all tissue compartments decreased in the ranges of 66%-79% and 65%-76%, respectively. CONCLUSIONS: Using microdialysis, we demonstrated a significant reduction of moxifloxacin Cmax and AUC0-24 in the spinal tissues when coadministered with rifampicin.

Hypertension Caused by Lenvatinib and Everolimus in the Treatment of Metastatic Renal Cell Carcinoma.

Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus proved effective when applied alone, but more effective when they were administered combined. Recently, both drugs were included in clinical trials, resulting in international clinical guidelines for the treatment of mRCC. In May 2016, lenvatinib was approved by the American Food and Drug Administration (FDA) for the use in combination with everolimus, as treatment of advanced renal cell carcinoma following one prior antiangiogenic therapy. A major problem of treating mRCC with lenvatinib and everolimus is the serious adverse event (AE) of arterial hypertension. During the treatment with everolimus and lenvatinib combined, 42% of the patients developed hypertension, while 10% of the patients treated with everolimus alone and 48% of the of the lenvatinib only treated patients developed hypertension. Lenvatinib carries warnings and precautions for hypertension, cardiac failure, and other adverse events. Therefore, careful monitoring of the patients is necessary.

Moxifloxacin Concentrations in the Knee Joint, Tibial Bone, and Soft Tissue When Combined with Rifampicin: A Randomized Porcine Microdialysis Study.

BACKGROUND: Peri and postoperative antibiotics are key adjuvant treatment tools in the management of periprosthetic joint infection (PJI). The aim of this study was to evaluate the effect of rifampicin on the area under the moxifloxacin concentration-time curve from 0 to 24 hours (AUC0-24) in the synovial fluid of the knee joint, tibial bone, and adjacent subcutaneous tissue under steady-state conditions using microdialysis in a porcine model. METHODS: Twenty female pigs were randomized to receive oral treatment with moxifloxacin monotherapy (Group A, n = 10) of 400 mg once daily for 3 days or a combination therapy (Group B, n = 10) of 400 mg of moxifloxacin once daily for 3 days and 450 mg of rifampicin twice daily for 7 days. Microdialysis was used for sampling the synovial fluid of the knee joint, tibial cancellous and cortical bone, and adjacent subcutaneous tissues. Plasma samples were taken as a reference. Measurements were obtained for 24 hours. RESULTS: Coadministration of moxifloxacin and rifampicin resulted in reductions of the moxifloxacin AUC0-24 in all targeted tissue compartments by 67% to 85% (p < 0.05). The corresponding change in plasma was 20% (p = 0.49). For both groups, the tissue penetration (the ratio of tissue free fraction AUC0-24 to plasma free fraction AUC0-24 [fAUCtissue/fAUCplasma]) was incomplete in all investigated compartments. The highest moxifloxacin tissue penetration was in the knee joint synovial fluid: 0.59 (Group A) and 0.24 (Group B). The lowest tissue penetration was in the cortical bone: 0.17 (Group A) and 0.03 (Group B). CONCLUSIONS: We found a significant reduction of the moxifloxacin concentration, expressed as the AUC0-24, in tissues relevant to acute PJI treatment when coadministered with rifampicin. CLINICAL RELEVANCE: The concentrations within the targeted tissue compartments were reduced significantly more than the concentrations in plasma, which may be particularly important as plasma concentrations are used in clinical practice to assess moxifloxacin treatment sufficiency.

Flucloxacillin bone and soft tissue concentrations assessed by microdialysis in pigs after intravenous and oral administration.

AIMS: Flucloxacillin is commonly administered intravenously for perioperative antimicrobial prophylaxis, while oral administration is typical for prophylaxis following smaller traumatic wounds. We assessed the time, for which the free flucloxacillin concentration was maintained above the minimum inhibitory concentration (fT > MIC) for methicillin-susceptible Staphylococcus aureus in soft and bone tissue, after intravenous and oral administration, using microdialysis in a porcine model. METHODS: A total of 16 pigs were randomly allocated to either intravenous (Group IV) or oral (Group PO) flucloxacillin 1 g every six hours during a 24-hour period. Microdialysis was used for sampling in cancellous and cortical bone, subcutaneous tissue, and the knee joint. In addition, plasma was sampled. The flucloxacillin fT > MIC was evaluated using a low MIC target (0.5 µg/ml) and a high MIC target (2.0 µg/ml). RESULTS: Intravenous administration resulted in longer fT > MIC (0.5 µg/ml) compared to oral administration, except for cortical bone. In Group IV, all pigs reached a concentration of 0.5 µg/ml in all compartments. The mean fT > MIC (0.5 µg/ml) was 149 minutes (95% confidence interval (CI) 119 to 179; range 68 to 323) in subcutaneous tissue and 61 minutes (95% CI 29 to 94; range 0 to 121) to 106 minutes (95% CI 76 to 136; range 71 to 154) in bone tissue. In Group PO, 0/8 pigs reached a concentration of 0.5 µg/ml in all compartments. For the high MIC target (2.0 µg/ml), fT > MIC was close to zero minutes in both groups across compartments. CONCLUSION: Although intravenous administration of flucloxacillin 1 g provided higher fT > MIC for the low MIC target compared to oral administration, concentrations were surprisingly low, particularly for bone tissue. Achievement of sufficient bone and soft tissue flucloxacillin concentrations may require a dose increase or continuous administration. Cite this article: Bone Joint Res 2021;10(1):60-67.

Real-Time Ultrasound/MRI Fusion for Suprasacral Parallel Shift Approach to Lumbosacral Plexus Blockade and Analysis of Injectate Spread: An Exploratory Randomized Controlled Trial.

Fused real-time ultrasound and magnetic resonance imaging (MRI) may be used to improve the accuracy of advanced image guided procedures. However, its use in regional anesthesia is practically nonexistent. In this randomized controlled crossover trial, we aim to explore effectiveness, procedure-related outcomes, injectate spread analyzed by MRI, and safety of ultrasound/MRI fusion versus ultrasound guided Suprasacral Parallel Shift (SSPS) technique for lumbosacral plexus blockade. Twenty-six healthy subjects aged 21-36 years received two SSPS blocks (20 mL 2% lidocaine-epinephrine [1 : 200,000] added 1 mL diluted contrast) guided by ultrasound/MRI fusion versus ultrasound. Number (proportion) of subjects with motor blockade of the femoral and obturator nerves and the lumbosacral trunk was equal (ultrasound/MRI, 23/26 [88%]; ultrasound, 23/26 [88%]; p = 1.00). Median (interquartile range) preparation and procedure times (s) were longer for the ultrasound/MRI fusion guided technique (686 [552-1023] versus 196 [167-228], p < 0.001 and 333 [254-439] versus 216 [176-294], p = 0.001). Both techniques produced perineural spread and corresponding sensory analgesia from L2 to S1. Epidural spread and lidocaine pharmacokinetics were similar. Different compartmentalized patterns of injectate spread were observed. Ultrasound/MRI fusion guided SSPS was equally effective and safe but required prolonged time, compared to ultrasound guided SSPS. This trial is registered with EudraCT (2013-004013-41) and ClinicalTrials.gov (NCT02593370).