Peter Frederik Horstmann

Pharmacokinetics of gentamicin eluted from a regenerating bone graft substitute: In vitro and clinical release studies

Objectives Deep bone and joint infections (DBJI) are directly intertwined with health, demographic change towards an elderly population, and wellbeing. The elderly human population is more prone to acquire infections, and the consequences such as pain, reduced quality of life, morbidity, absence from work and premature retirement due to disability place significant burdens on already strained healthcare systems and societal budgets. DBJIs are less responsive to systemic antibiotics because of poor vascular perfusion in necrotic bone, large bone defects and persistent biofilm-based infection. Emerging bacterial resistance poses a major threat and new innovative treatment modalities are urgently needed to curb its current trajectory. Materials and Methods We present a new biphasic ceramic bone substitute consisting of hydroxyapatite and calcium sulphate for local antibiotic delivery in combination with bone regeneration. Gentamicin release was measured in four setups: 1) in vitro elution in Ringer’s solution; 2) local elution in patients treated for trochanteric hip fractures or uncemented hip revisions; 3) local elution in patients treated with a bone tumour resection; and 4) local elution in patients treated surgically for chronic corticomedullary osteomyelitis. Results The release pattern in vitro was comparable with the obtained release in the patient studies. No recurrence was detected in the osteomyelitis group at latest follow-up (minimum 1.5 years). Conclusions This new biphasic bone substitute containing antibiotics provides safe prevention of bone infections in a range of clinical situations. The in vitro test method predicts the in vivo performance and makes it a reliable tool in the development of future antibiotic-eluting bone-regenerating materials. Cite this article: M. Stravinskas, P. Horstmann, J. Ferguson, W. Hettwer, M. Nilsson, S. Tarasevicius, M. M. Petersen, M. A. McNally, L. Lidgren. Pharmacokinetics of gentamicin eluted from a regenerating bone graft substitute: In vitro and clinical release studies. Bone Joint Res 2016;5:427–435. DOI: 10.1302/2046-3758.59.BJR-2016-0108.R1.

Low Infection Rate after Tumor Hip Arthroplasty for Metastatic Bone Disease in a Cohort Treated with Extended Antibiotic Prophylaxis

Background. Compared to conventional hip arthroplasty, endoprosthetic reconstruction after tumor resection is associated with a substantially increased risk of periprosthetic joint infection (PJI), with reported rates of around 10% in a recent systematic review. The optimal duration of antibiotic prophylaxis for this patient population remains unknown. Material and Methods. To establish the infection rate associated with prolonged antibiotic prophylaxis in our department, we performed a retrospective review of all adult patients who underwent endoprosthetic reconstruction of the proximal femur after tumor resection for metastatic bone disease during a 4-year period from 2010 to 2013 (n = 105 patients). Results. Intravenous antibiotic prophylaxis was administrated for an extended duration of a mean of 7.4 days. The overall infection rate was 3.6% (4/111 implants), infection free survival was 96% at 2 years, and the risk of amputation associated with infection was 25% (1/4 patients). Discussion. Preemptive eradication of bacterial contamination may be of value in certain clinical situations, where the risk level and consequences of implant-associated infection are unacceptable. Our findings suggest that extended postoperative antibiotic prophylaxis may reduce the risk of PJI in patients undergoing tumor resection and endoprosthetic replacement for metastatic bone disease associated impending or de facto pathologic fractures of the proximal femur.

Antibiotic Containing Bone Substitute in Major Hip Surgery: A Long Term Gentamicin Elution Study

Objectives: The objective is to present the antibiotic elution from a locally implanted gentamicin containing hydroxyapatite and calcium sulphate bone substitute with an extended follow up of 30 days. We also compare the pharmacokinetics of the ceramic bone substitute with a published study on gentamicin containing poly (methyl methacrylate) (PMMA) bone cement used in primary total hip arthroplasty. Methods: Gentamicin release was measured in the urine for a month and the serum for 4 days in 10 patients operated for trochanteric hip fractures and 10 patients in uncemented hip revisions. 17 patients were followed up at one year and 3 patients at 6 months. Results and Discussion: The gentamicin concentrations measured in serum were low and approximately 100 times less than in urine during the first days, indicating high local concentrations at the implant site. The elution from the biphasic bone substitute showed a stronger burst and higher gentamicin concentrations for the first week compared to that reported for PMMA used in hip arthroplasty. Also, for the bone substitute a complete gentamicin elution was obtained after 30 days, while for the PMMA cement sub-inhibitory MIC levels of gentamicin were still present in urine 60 days past surgery. No infections were detected. Conclusions: A new biphasic bone substitute containing antibiotics could potentially be used to prevent infection in patients treated for trochanteric hip fractures or uncemented hip revisions. The gentamicin elution from the bone substitute is efficient with high initial local gentamicin concentrations and complete release at 30 days.

Persistent Wound Drainage After Tumor Resection and Endoprosthetic Reconstruction of the Proximal Femur

Purpose: To examine the prevalence of prolonged wound drainage (PWD) after tumor resection and endoprosthetic reconstruction of the hip. Methods: Retrospective review of 86 consecutive patients with metastatic bone disease, malignant hematologic bone disease or bone sarcoma, treated with tumor resection and subsequent endoprosthetic reconstruction of the proximal femur, between 2010 and 2012, in a single center. Results: PWD for 7 days or more was observed in 41 cases (48%). The wounds only ceased oozing after a mean of 8.4 days, leading to prolonged administration of prophylactic antibiotics (mean 8.7 days) and length of hospital stay (mean 10.2 days). Total femur replacement, bone sarcoma and additional pelvic reconstruction were identified as significant independent risk factors for an even longer duration of PWD. Conclusion: Compared to conventional hip arthroplasty, PWD appears to be significantly more prevalent in patients undergoing tumor arthroplasty procedures of the hip. Given the potentially increased risk for periprosthetic joint infection (PJI), increased awareness, identification and implementation of adequate strategies for prevention and treatment of this avoidable complication are warranted.

Early Clinical and Radiological Experience with a Ceramic Bone Graft Substitute in the Treatment of Benign and Borderline Bone Lesions

Substitutes for bone grafts experience increasing popularity, but the need for defect-filling following simple curettage of benign bone lesions is controversial. In this study, we wish to objectively report the radiological changes following bone defect-filling using a composite ceramic bone graft substitute, as well as the clinical results and complications. We evaluated 35 surgically treated benign bone lesions with subsequent defect-filling using two variants of a composite ceramic bone graft substitute (CERAMENT|BONE VOID FILLER or CERAMENT|G, BONESUPPORT AB, SWEDEN). After one year, a normal cortical thickness surrounding the defect was seen in approximately 80% of patients. Inside the defect-cavity, an almost complete product-resorption was seen after one year. The most common complication was a post-operative inflammatory soft-tissue reaction, seen in 7 patients (20%), which resolved without further treatment, although short-term antibiotic treatment was initiated at a local hospital in 6 patients, due to suspected wound infection. In summary, cortical thickness most commonly normalizes after bone tumor removal and filling of the bone defect using this particular composite ceramic bone graft substitute. The ceramic substitute undergoes resorption, which causes progressive changes in the radiological appearance inside the bone defect.

Comparison of two alternative wound closure methods for tumor arthroplasty of the hip: A frequency matched cohort study

Objective: To examine the effect of an alternative wound closure method after tumor arthroplasty of the hip compared to routine wound closure with skin staples. Method: Single center, frequency matched cohort study. We reviewed all patients who underwent tumor resection and endoprosthetic reconstruction of the proximal femur for pathologic fracture due to metastatic bone disease or malignant hematologic bone disease at our center between 2010 and 2014. All patients treated with occlusive wound closure (OWC), a combination of intradermal suture, Steri-Strips™, and an occlusive skin adhesive, during this period (n = 35), were compared to an equally sized frequency matched group of patients having undergone routine wound closure with conventional skin staples. Results: Patients with OWC were significantly faster to achieve dry wound status and consequently had significantly shorter administration of antibiotics and hospital stay. Compared to the patients with conventional wound closure with staples, their wounds were already dry after a mean 3.4 days (vs. 6.7 days [95%CI: 3–3.8 vs. 5.5–7.9], p < 0.0001), they received antibiotics for a mean 4.2 days (vs. 6.8 days [95%CI: 3.7–4.8 vs. 5.5–8.0], p < 0.0003) and their mean hospital stay was 6.3 days (vs. 8.0 days [95%CI: 5.5–7 vs. 6.8–9.3], p < 0.015). Prolonged wound discharge (PWD) for 7 days or more was observed in 34% of patients (n = 12) in the conventional group, whereas this complication was completely absent (n = 0) in the investigational group. For every three patients treated with OWC, one complication of PWD over 7 days is avoided (number needed to treat = 3). Conclusion: Compared to conventional staples, OWC appears to significantly reduce wound complications, use of antibiotics, and hospital stay in patients undergoing tumor arthroplasty procedures of the hip. As such, it may also contribute to a reduction of the substantially increased risk for prosthetic joint infection in this patient population.

Natural Course of Local Bone Mineralization After Treatment of Benign or Borderline Bone Tumors and Cysts With a Composite Ceramic Bone Graft Substitute

After surgical bone tumor removal, filling of the bone defect is frequently performed using a bone graft or bone graft substitute. During follow-up, precise quantification of changes in bone mineral density, within the treated bone defect, is very difficult using conventional X-ray examinations. The objectives of this study were to characterize the pattern of resorption/biodegradation of a composite calcium sulfate/hydroxyapatite bone graft substitute and to quantify the bone defect healing with repeated dual-energy X-ray absorptiometry (DXA) measurements. Seventeen patients treated for 18 benign bone lesions, with subsequent defect filling using 2 variants of a composite ceramic bone graft substitute (CERAMENT™|BONE VOID FILLER or CERMAMENT™|G, BONESUPPORT AB, Lund, Sweden), were scanned postoperatively and after 2, 6, 12, 26, and 52 wk using DXA. After an initial increase in bone mineral density after implantation of the bone graft substitute, bone mineral density decreased in the bone defect region throughout the 52 wk: rapidly in the first 12 wk and slower in the remaining weeks. Despite this continuous decrease, bone mineral density remained, on average, 25% higher in the operated extremity, compared with the nonoperated extremity, after 52 wk. The observed pattern of reduction in bone mineral density is consistent with the anticipated resorption of calcium sulfate within the bone graft substitute during the first 12 wk after surgery. We believe the DXA technique provides a precise method for quantification of bone graft resorption, but for evaluation of new bone formation, 3-dimensional imaging is needed.

Patient survival following joint replacement due to metastatic bone disease – comparison of overall patient and prostheses survival between cohorts treated in two different time-periods

Abstract Background: Improvements in medical treatment for cancer have increased survival of cancer patients. We hypothesize that improvement in cancer treatment is reflected in increased survival after surgical intervention for metastatic bone disease (MBD) and that subsequent revision surgery does not pose a risk for survival. Methods: We identified a retrospective consecutive cohort who received bone resection and reconstruction (BRR) with implants (including total joint replacements (with or without wide resection) or bone reconstruction with an intercalary spacer or revisions procedures for failed implants with BBR technique) due to MBD from 2003 to 2008 (early cohort) and 2009 to 2013 (late cohort) at a tertiary referral center. We registered epidemiological data, type of implant (primary or a revision implant), patient survival (Kaplan–Meier), implant survival (competing risk analysis) and complications to surgery. Results: Three hundred and eleven procedures were performed in 291 patients (289 primary BRR (270 patients, early cohort n = 130 late cohort n = 140) and 22 revision BRR (21 patients)). Overall survival was 44% (95% confidence intervals (95% CI): 39–50) and 32% (95% CI: 27–38) after 1 and 2 years. No difference in survival between the early and late cohort was found (p = .458), or between primary and revision BRR (p = .465). Time from diagnosis of cancer to surgery was shorter in the early cohort (p < .001). The cumulative incidence of failure of implant was 2% (95% CI: 0–3%) at 1 year and 3% (95% CI: 1–6%) at 2 years. One year cumulative implant failure for revision implants was 5% (95% CI: 0–13%) at 1 and 2 years. The risk of failure was not statistical significant between primary and revision implant (p = .293) in competing risk analysis. Discussion: We were not able to identify an increased survival after surgery for MBD over time, however, we found an increased interval from diagnosis to surgery for MBD. This study suggests that revision surgery for MBD does not pose a risk for survival.

Survival and prognostic factors at time of diagnosis in high-grade appendicular osteosarcoma: a 21 year single institution evaluation from east Denmark

Abstract Background: Survival of patients with high-grade osteosarcoma (HOS), the most common primary bone cancer, has not improved significantly the last 30 years and the disease remains a major challenge. The purpose of this study is to evaluate survival in relation to prognostic factors at time of diagnosis among patients diagnosed with primary appendicular HOS in East Denmark between 1990 and 2010. Material and methods: 101 patients (median age = 20 years, female/male ratio = 56/45) diagnosed with primary appendicular high-grade osteosarcoma between 1990 and 2010 were included in this study. Initially, 156 patients diagnosed with osteosarcoma between 1990 and 2010 were identified through the population based Regional Database of Pathology, which covers a population of approximately 2.7 million (east Denmark). 55 patients were excluded due to (A) tumor was low grade (n = 22), (B) located in axial skeleton (n = 18), (C) incorrect diagnosis (n = 11) or (D) biopsy represented a tumor relapse from a former primary osteosarcoma (n = 4). Overall survival was evaluated using the Kaplan–Meier survival analysis and log-rank test. Prognostic factors were analyzed using uni- and multivariate cox-regression method with variables scored equally in the model. p Values <.05 were considered statistically significant. Results: The probability of 5- and 10-year survival was 51% (95% CI: 41–61) and 46% (95% CI: 36–56), respectively. Metastatic stage at diagnosis and tumor size ≥10 cm measured radiologically at the largest diameter were independent prognostic factors for decreased survival with significant increased hazard-risks of 3.5 (95% CI: 1.9–6.5) and 1.97 (95% CI: 1.1–3.6), respectively. Discussion: In this single institution evaluation of primary appendicular HOS we found 5-and 10-year survival rates consistent with international standards for this patient group. Distant metastases and tumor size ≥10 cm at the time of diagnosis were independent prognostic factors for decreased survival in our cohort. These results underline the importance of awareness and early referral from the primary sector.