Penicillin Concentrations in Oropharyngeal and Frontal Sinus Tissue Following Enteral and Intravenous Administration Measured by Microdialysis in a Porcine Model.

BACKGROUND: Penicillin may be administered enterally or intravenously for the treatment of bacterial infections within the oropharynx and the frontal sinuses. We aimed to assess and compare penicillin concentrations in oropharyngeal and frontal sinus tissues following enteral and intravenous administration in a porcine model. METHOD: Twelve pigs were randomized to receive either enteral (0.8 g Penicillin V) or intravenous (1.2 g Penicillin G) penicillin. Microdialysis was used for sampling in oropharyngeal and frontal sinus tissues during a six-hour dosing interval. In addition, plasma samples were collected. The primary endpoints were time with drug concentration above the minimal inhibitory concentration (T>MIC) for two MIC targets: 0.125 (low target) and 0.5 (high target) µg/mL (covering Group A Streptococci, Fusobactarium necrophorum, Streptococcus pneumoniae and Hemophilus influenza) and attainment of these treatment targets for ≥50%T>MIC. RESULTS: For both the low and high MIC targets, intravenous administration resulted in higher T>MIC in oropharyngeal and frontal sinus tissues compared to enteral administration. In oropharyngeal tissue, the treatment target (≥50% T>MIC) was achieved for both the low target (96%) and high target (68%) when penicillin was administrated intravenously. In frontal sinus tissue, the treatment target was reached for the low target (70%), but not the high target (35%) when administered intravenously. None of the two tissues reached the treatment targets when penicillin was administered enterally. CONCLUSION: Intravenous administrated penicillin in standard dosage is superior to enteral administration of penicillin in standard dosage in achieving clinically important T>MIC as the majority of targets were achieved following intravenously administration, while none of the targets were achieved following enteral administration. These results support the general notion of higher tissue concentrations following intravenous compared to enteral administration.

Doxorubicin concentrations in bone tumour-relevant tissues after bolus and continuous infusion: a randomized porcine microdialysis study.

PURPOSE: Doxorubicin is a widely used chemotherapeutic drug that can be administered intravenously as both a bolus infusion and a continuous infusion. The latter is believed to lower the risk of cardiotoxicity, which is a critical long-term complication of doxorubicin treatment. The local tissue concentrations of doxorubicin will be reflected in both treatment efficacy and toxicity, but very limited information is available. The aim of this study was to measure the concentration of doxorubicin after continuous and bolus infusion in tissue compartments around a typical location of a bone tumour. METHODS: Sixteen pigs (female, Danish Landrace, mean weight 77 kg) were randomized into two groups of eight. Both groups received an intravenous infusion of 150 mg doxorubicin; Group 1 received a bolus infusion (10-15 min) and Group 2 received a continuous infusion (6 h). Before infusion, microdialysis catheters were placed intravenously and in four bone tumour-relevant tissue compartments (cancellous bone, subcutaneous tissue, synovial fluid of the knee joint and muscle tissue). Sampling was done (n = 15) over 24 h, and venous blood samples were collected as a reference. RESULTS: Area under the concentration-time curve (AUC0-24 h) for plasma (total concentration) was significantly different between the two groups, while peak drug concentration (Cmax) was significantly higher in two compartments (plasma and synovial fluid of the knee joint) in Group 1 compared to Group 2. Overall, the unbound tissue concentrations were extremely low with values below 0.20 µg/mL. CONCLUSION: The pharmacokinetic profile for doxorubicin in the investigated tissues is very similar when comparing bolus and 6 h continuous infusion.

Microdialysis as a sampling tool for the chemotherapeutic agent Doxorubicin.

Doxorubicin is a chemotherapeutic agent used for more than fifty years to treat a great variety of cancers in both children and adults. Despite hereof, pharmacokinetic knowledge is almost solely based on systemic plasma concentrations. Microdialysis is a catheter-based pharmacokinetic sampling tool enabling simultaneous target site sampling of unbound molecules of interest. The aim of this study was to thoroughly evaluate the feasibility of applying microdialysis for sampling of Doxorubicin in both in vitro experiments and an in vivo setting. Doxorubicin relative recovery by gain and by loss was tested for different catheter types, perfusion fluids, concentrations and collection vials. Adsorption tests revealed polystyrene/santoprene vials to be the biggest contributor of unwanted adsorption between Doxorubicin and the microdialysis equipment, and confirmed LoBind Eppendorf tubes to be a suitable alternative. The methodological combination of polyamide membranes, saline as perfusion fluid and LoBind Eppendorf sampling tubes demonstrated no statistically significant differences for relative recovery by gain and by loss, and the relative recovery was also found to be concentration independent. We conclude, that a proper microdialysis set-up can be used to collect samples containing concentrations of the chemotherapeutic drug Doxorubicin in vitro and in vivo, which encourage future pharmacokinetic studies to evaluate current treatment regimens to find the most effective and least toxic anti-neoplastic treatment for the patients.

Piperacillin Steady State Concentrations in Target Tissues Relevant for PJI Treatment-A Randomized Porcine Microdialysis Study Comparing Continuous Infusion with Intermittent Short-Term Infusion.

(1) Introduction: Piperacillin is a common antibiotic choice in the treatment of periprosthetic joint infections (PJI) caused by Pseudomonas aeruginosa. The aim of this study was to assess and compare the time with free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) at steady state in target tissues relevant for PJI treatment following continuous and intermittent short-term infusion. (2) Methods: 16 pigs were randomized to receive either continuous or intermittent short-term infusion of piperacillin. Steady state piperacillin concentrations were assessed using microdialysis in tibial cortical bone, tibial cancellous bone, synovial fluid of the knee joint, and subcutaneous tissue. MIC-targets of 4, 8, 16, and 64 mg/L were applied. Plasma samples were obtained as reference. (3) Results: Continuous infusion resulted in longer fT > MIC for MIC targets of 4 mg/L and 8 mg/L compared to intermittent short-term infusion in all compartments with the exception of tibial cortical bone. For the MIC-target of 16 mg/L, continuous infusion resulted in a longer fT > MIC in all compartments except for the bone compartments. No differences between groups were seen when applying a MIC-target of 64 mg/L. (4) Conclusions: An aggressive dosing strategy may be necessary to obtain sufficient piperacillin concentrations in all bone compartments, particularly if more aggressive targets are applied. Based on the present study, continuous infusion should be considered in the treatment of PJI.

Steady-State Piperacillin Concentrations in the Proximity of an Orthopedic Implant: A Microdialysis Porcine Study.

Implant-associated osteomyelitis is one of the most feared complications following orthopedic surgery. Although the risk is low, sufficient antibiotic protection of the implant surface is important. The aim of this study was to assess steady-state piperacillin concentrations in the proximity of an orthopedic implant. Time above the minimal inhibitory concentration (fT>MIC) was evaluated for MIC of 8 (low target) and 16 µg/mL (high target). Six female pigs received an intravenous bolus infusion of 4 g/0.5 g piperacillin/tazobactam over 30 min every 6 h. Steady state was assumed achieved in the third dosing interval (12-18 h). Microdialysis catheters were placed in a cannulated screw in the proximal tibial cancellous bone, in cancellous bone next to the screw, and in cancellous bone on the contralateral tibia. Dialysates were collected from time 12 to 18 h and plasma samples were collected as reference. For the low piperacillin target (8 µg/mL), comparable mean fT>MIC across all the investigated compartments (mean range: 54-74%) was found. For the high target (16 µg/mL), fT>MIC was shorter inside the cannulated screw (mean: 16%) than in the cancellous bone next to the screw and plasma (mean range: 49-54%), and similar between the two cancellous bone compartments. To reach more aggressive piperacillin fT>MIC targets in relation to the implant, alternative dosing regimens such as continuous infusion may be considered.

Intermittent Short-Term Infusion vs. Continuous Infusion of Piperacillin: Steady State Concentrations in Porcine Cervical Spine Tissue Evaluated by Microdialysis.

Background: Piperacillin is a central drug in the treatment of Pseudomonas aeruginosa spondylodiscitis. Intermittent short-term infusion (STI) remains standard treatment in most centres, although the application of continuous infusion (CI) has shown promising results in other clinical settings. We aimed to evaluate time above the minimal inhibitory concentration (fT > MIC) of the free fraction of piperacillin in steady state conditions in porcine cervical spine tissue following CI and STI using microdialysis with MIC targets of 4, 8, and 16 µg/mL. Methods: 16 female pigs were randomized to receive piperacillin/tazobactam as STI (4/0.5 g every 6 h) or CI (4/0.5 g as a bolus followed by 12/1.5 g) for 18 h. Microdialysis catheters were placed for sampling of piperacillin concentrations from the intervertebral disc, vertebral cancellous bone, paravertebral muscle, and adjacent subcutaneous tissue during the third dosing interval (12−18 h). Blood samples were collected as reference. Results: CI resulted in fT > MIC > 82% across all compartments and targets, except for intervertebral disc (37%) and vertebral cancellous bone (28%) at MIC = 16 µg/mL. In Group STI, >72% fT > MIC was reached for MIC = 4 µg/mL in all investigated compartments, while for MIC = 16 µg/mL only subcutaneous tissue exhibited fT > MIC > 50%. Conclusion: CI of piperacillin resulted in higher fT > MIC compared to STI infusion across the investigated tissues and targets. CI should therefore be considered in spondylodiscitis cases requiring piperacillin treatment.

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.

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

Background and purpose - Tourniquet is widely used in orthopedic surgery to reduce intraoperative bleeding and improve visualization. We evaluated the effect of tourniquet application on peri- and postoperative cefuroxime concentrations in subcutaneous tissue, skeletal muscle, calcaneal cancellous bone, and plasma. The primary endpoint was the time for which the free cefuroxime concentration was maintained above the clinical breakpoint minimal inhibitory concentration (T > MIC) for Staphylococcus aureus (4 µg/mL).Patients and methods - 10 patients scheduled for hallux valgus or hallux rigidus surgery were included. Microdialysis catheters were placed for sampling of cefuroxime concentrations bilaterally in subcutaneous tissue, skeletal muscle, and calcaneal cancellous bone. A tourniquet was applied on the thigh of the leg scheduled for surgery (tourniquet duration time [range]: 65 minutes [58-77]). Cefuroxime (1.5 g) was administered intravenously 15 minutes prior to tourniquet inflation, followed by a second dose 6 hours later. Dialysates and venous blood samples were collected for 12 hours.Results - A cefuroxime concentration of 4 µg/mL was reached within 23 minutes in all compartments and patients. For cefuroxime the T > MIC (4 µg/mL) ranged between 4.8 and 5.4 hours across compartments, with similar results for the tourniquet and non-tourniquet leg. Comparable T > MIC and penetration ratios were found for the first and second dosing intervals.Interpretation - Administration of cefuroxime (1.5 g) 15 minutes prior to tourniquet inflation is safe in order to achieve tissue concentrations above 4 µg/mL throughout surgery. A tourniquet application time of approximately 1 hour did not affect the cefuroxime tissue penetration in the following dosing interval.

Bone mineral density changes in a free vascularised fibular graft in the distal femoral bone after osteosarcoma in a 10-year-old boy: a 7-year follow-up.

A 10-year-old boy presented with continuous reports of pain located to the left knee. Imaging revealed a sclerotic process in the left distal femur, and biopsies were consistent with chondroblastic osteosarcoma. As part of standard treatment the patient underwent neoadjuvant chemotherapy followed by limb sparring surgery and adjuvant chemotherapy. The entire tumour was excised and femoral bone reconstruction was performed with a double barrel free vascularised fibular graft. Bone mineral density (BMD) can be decreased in childhood survivors of cancer. The patient was followed for 7 years with dual-energy X-ray absorptiometry scans in order to assess BMD and graft adaption. Despite two accidental fractures to the graft region local and global BMD underwent an overall increase. Approximately 7 years after tumour resection the patient had a global Z-score of 0.2, which is considered within normal range.

Tourniquet-induced ischemia and reperfusion in subcutaneous tissue, skeletal muscle, and calcaneal cancellous bone.

This study aimed to evaluated ischemic metabolites in subcutaneous tissue, skeletal muscle, and calcaneal cancellous bone before, during, and after tourniquet application in a simultaneous paired comparison of tourniquet-exposed and non-tourniquet-exposed legs. Ten patients scheduled for hallux valgus or hallux rigidus surgery were included. Microdialysis catheters were placed to simultaneously and continuously sample the metabolites glucose, lactate, pyruvate, and glycerol bilaterally for 12 h in subcutaneous tissue, skeletal muscle, and calcaneal cancellous bone. A tourniquet was applied on the leg planned for surgery (inflation time: 15 min, mean tourniquet duration time (range): 65 (58;77) min). During tourniquet inflation, a 2- to 3-fold increase of the mean lactate/pyruvate ratio was found for all investigated tissues in the tourniquet-exposed leg compared with the non-tourniquet-exposed leg. The lactate/pyruvate ratio recovery time after tourniquet release was within 30 min for skeletal muscle, 60 min for subcutaneous tissue, and 130 min for calcaneal cancellous bone. Only the tourniquet-exposed skeletal muscles were found to be ischemic during tourniquet inflation, defined by a significant increase of the lactate/pyruvate ratio exceeding the ischemic cutoff level of 25; however, this level decreased below 25 immediately after tourniquet release. The glycerol ratio increased instantly after inflation in the tourniquet-exposed leg in skeletal muscle and subcutaneous tissue, and recovered within 60 (skeletal muscle) and 130 min (subcutaneous tissue) after tourniquet release. These findings suggest that applying tourniquet for approximately 1 h results in limited tissue ischemia and cell damage in subcutaneous tissue, skeletal muscle, and calcaneal cancellous bone.

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.

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

BACKGROUND CONTEXT: Postoperative pyogenic spondylodiscitis is associated with prolonged antimicrobial therapy and high relapse rates. Cefuroxime is a time-dependent antimicrobial widely used for intravenous perioperative prophylaxis in spine surgery. A previous study has indicated that a single dose of cefuroxime (1.5 g) provides insufficient spine tissue concentrations for spine procedures lasting more than 2 to 3 hours. PURPOSE: To evaluate the time with concentrations above relevant minimal inhibitory concentrations (T>MIC) in plasma, subcutaneous adipose tissue, vertebral cancellous bone, and intervertebral disc after a twofold increase of the standard dosage of 1.5 g cefuroxime given as one double dose (1×3 g) or two single doses (2×1.5 g) with a four-hour interval. METHODS: Sixteen pigs were randomized into two groups: Group 1 received one double dose of cefuroxime (1×3 g) as an intravenous bolus and Group 2 received two single doses of cefuroxime (2×1.5 g) as an intravenous bolus with a four-hour interval. Cefuroxime measurements were obtained from plasma, subcutaneous adipose tissue, vertebral cancellous bone, and intervertebral disc for eight hours thereafter. Microdialysis was applied for sampling in solid tissues. The cefuroxime concentrations were determined using ultra-high performance liquid chromatography. This work was supported by grants from the Health Research Foundation of Central Denmark Region (Level E). The funding source did not play any role in the investigation. RESULTS: The time with concentrations above the Staphylococcus aureus clinical breakpoint minimal inhibitory concentration of 4 µg/mL was higher in all compartments for Group 2 compared to Group 1. The mean T>MIC (4 µg/mL) in all compartments ranged between 47% and 67% for Group 1 and 72% and 92% for Group 2. Furthermore, a delayed tissue penetration into all tissues for both groups was demonstrated. CONCLUSIONS: This study suggests that cefuroxime should be given at least 45 minutes prior to spine procedures and as two single doses at a maximum interval of four hours for extended spine procedures. Clinical studies verifying these results are warranted. CLINICAL SIGNIFICANCE: Administering cefuroxime as two single doses (2×1.5 g) with a four-hour interval compared to one double dose (1×3 g) resulted in higher T>MIC. Furthermore, we found delayed and incomplete cefuroxime tissue penetration.