Florian M. Kovar

Penetration of Linezolid into Soft Tissues of Healthy Volunteers after Single and Multiple Doses

ABSTRACT The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC0-8) for tissue to the AUC0-8 for free plasma were 1.4 ± 0.3 (mean ± standard deviation) and 1.3 ± 0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9 ± 0.2 and 1.0 ± 0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC0-24) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria.

Penetration of Moxifloxacin into Healthy and Inflamed Subcutaneous Adipose Tissues in Humans

ABSTRACT The present study addressed the ability of moxifloxacin to penetrate into healthy and inflamed subcutaneous adipose tissues in 12 patients with soft tissue infections (STIs). Penetration of moxifloxacin into the interstitial space fluid of healthy and inflamed subcutaneous adipose tissues was measured by use of in vivo microdialysis following administration of a single intravenous dosage of 400 mg in six diabetic and six nondiabetic patients with STIs. For the entire study population, the mean time-concentration profile of free moxifloxacin in plasma was identical to the time-concentration profile of free moxifloxacin in tissue (P was not significant). For healthy and inflamed adipose tissues for the diabetic subgroup, the mean moxifloxacin areas under the concentration-time curves (AUCs) from 0 to 8 h (AUC0-8s) were 8.1 ± 7.1 and 3.7 ± 1.9 mg·h/liter, respectively (P was not significant). The ratios of the mean AUC0-8 for inflamed tissue/AUC0-8 for free moxifloxacin in plasma were 0.5 ± 0.4 for diabetic patients and 1.2 ± 0.8 for nondiabetic patients (P was not significant). The ratios of the AUCs from 0 to 24 h for free moxifloxacin in plasma/MIC at which 90% of isolates are inhibited were >58 and 121 h for Streptococcus species and methicillin-sensitive Staphylococcus aureus, respectively. Concentrations of moxifloxacin effective against clinically relevant bacterial strains are reached in plasma and in inflamed and healthy adipose tissues. Thus, the pharmacokinetics of moxifloxacin in tissue and plasma support its use for the treatment of STIs in diabetic and nondiabetic patients.

Nonoperative management of odontoid fractures using a halothoracic vest.

OBJECTIVEDespite various reports in the literature, the appropriate treatment of Type II odontoid fractures remains controversial. Although there is an increasing tendency toward surgical treatment of these fractures in recent years, nonoperative treatment strategies are still regarded as a practicable method, particularly in elderly patients with significant comorbidities. One purpose of this study was to determine the functional and radiographic long-term results after rigid immobilization of Type II odontoid fractures using a halothoracic vest. The second aim was to present a case-control series of patients with nonunion of Type II odontoid fractures compared with patients with successful fracture healing to determine specific risk factors for failure of halo immobilization. METHODSWe reviewed the clinical and radiographic records of 90 patients with an average age of 69 years at the time of injury who had undergone nonoperative treatment of odontoid fractures using a halothoracic vest between 1988 and 2004. To identify potential risk factors for failure of halo fixation, patients were divided into “cases” and “controls.” Cases were defined as patients with nonfusion after halo immobilization, and controls were patients with successful fracture healing attained with this treatment option. RESULTSSeventy-five patients returned to their preinjury activity level and were satisfied with their treatment. The Smiley-Webster scale showed an overall functional outcome score of 1.64. Successful fracture healing was achieved in 76 patients (84%). In 14 patients, nonunion was diagnosed by standard x-rays and additional computed tomographic scans within 6 to 12 months after trauma. Referring to possible risk factors for failure of halo fixation, nonunion was found significantly more often in older patients and in those with displaced fractures of the odontoid. Secondary loss of reduction and delay of treatment were identified as further risk factors for nonfusion. CONCLUSIONWith regard to successful fracture healing and functional results of the patients, we had a satisfactory outcome after halo fixation of Type II odontoid fractures. Although a fusion rate of 84% should not be deemed as optimal, nonoperative management of these fractures using a halothoracic vest seems to be an appropriate treatment strategy in patients who are not suitable for surgical treatment.

Management and outcome of periprosthetic fractures after total knee arthroplasty.

BACKGROUND The incidence of periprosthetic fractures after total knee arthroplasty is continuously rising because of an increasing number of knee joint replacements and an enhanced survivorship of the elderly population after knee arthroplasty. The purpose of this study was to analyze the practicability and effectiveness of the various treatment methods for management of periprosthetic fractures after total knee arthroplasty, and to determine the clinical and radiographic long-term results of patients following surgical and nonoperative treatment of these injuries. METHODS We reviewed the clinical and radiographic records of 41 patients (31 women and 10 men; average age, 78.6 years) with periprosthetic fractures after total knee arthroplasty between 1992 and 2008. Thirty-seven patients showed a periprosthetic fracture of the distal femur, and four patients had a periprosthetic proximal tibial fracture. Thirty-six patients underwent operative stabilization by plate fixation (n = 18), intramedullary nailing (n = 15) or revision arthroplasty (n = 3), and five patients were treated nonoperatively by long-term cast immobilization. RESULTS Twenty-eight patients returned to their preinjury activity level and were satisfied with their clinical outcome. In 10 patients, we saw a relevant decrease of knee function and severe limitations in gait and activities of daily living. Three patients died related to surgery. Successful fracture healing within 6 months was achieved in 33 (87%) of 38 patients. Failures of reduction or fixation occurred in 8 (21%) of 38 patients. Reoperation due to technical failures was necessary in three patients. CONCLUSIONS Compared with current data in literature, we had a satisfactory outcome in following individualized treatment of periprosthetic fractures after knee joint replacement. Referring to the wide field of treatment options and high rates of complications, periprosthetic femoral fractures around the knee commonly constitute a challenging problem for the treating surgeons and require an adequate analysis of fracture etiology and a corresponding transfer into an individual treatment concept.

The tumor necrosis factor alpha -308 G/A polymorphism does not influence inflammation and coagulation response in human endotoxemia.

Tumor necrosis factor (TNF)-&agr; plays a major role in the immune system. Release of proinflammatory cytokines, such as TNF-&agr; and interleukin 6, by macrophages and other cells occurs in response to bacterial products. It has been reported that the TNF-&agr; −308 G/A polymorphism in the TNF-&agr; gene determines basal TNF-&agr; levels. We hypothesized that it may also be associated with the degree of inflammatory response in a well-standardized model of systemic inflammation. Eighty-seven young men (age range, 19-35 years) received 2 ng/kg i.v. endotoxin (lipopolysaccharide [LPS]). The TNF-&agr; promoter genotype was analyzed on a TaqMan genomic analyzer. Inflammation markers (interleukin 6, TNF-&agr;), temperature, and coagulation markers (prothrombin fragment F1+2, D-dimer) were measured at 0, 2, 6, and 24 h after LPS infusion. Tumor necrosis factor-&agr; plasma concentrations increased from a baseline 1.3 ng/L (range, 0.8-3.1 ng/L) before LPS infusion to a peak of 57.5 ng/L (range, 10.8-131.4 ng/L) at 2 h after LPS and then decreased continually to 10.8 ng/L (range, 4.7-16.5 ng/L) after 6 h and returned to baseline values after 24 h (1.9 ng/L [range, 1.1-3.9 ng/L]). We observed no significant differences in TNF-&agr; baseline levels or in response to LPS after stratification of the data according to TNF-&agr; genotype. Basal and peak values of selected inflammatory and coagulation markers were not different between wild-type TNF-&agr; −308 individuals (GG) and carriers of the TNF-&agr; −308 mutant allele (GA and AA). The TNF-&agr; −308 G/A polymorphism does not contribute significantly to the individual variability of systemic TNF-&agr; plasma concentrations after endotoxin challenge. Thus, if any, the impact of the TNF-&agr; −308 G/A polymorphism on systemic endotoxin-triggered inflammation seems to be limited.

Clinical and Radiological Long-term Outcomes After Matrix-Induced Autologous Chondrocyte Transplantation A Prospective Follow-up at a Minimum of 10 Years

Background: It is unclear whether matrix-associated autologous chondrocyte transplantation (MACT) results in objective and subjective clinical improvements at 10 years after surgery. Hypothesis: Matrix-associated autologous chondrocyte transplantation will result in clinical and radiological improvements in patients with symptomatic, traumatic chondral defects of the knee joint. Study Design: Case series; Level of evidence, 4. Methods: A total of 16 patients with chondral defects of the knee were treated with MACT between November 2000 and April 2002 and evaluated for up to 10 years after the intervention. The International Knee Documentation Committee (IKDC) form, Knee Injury and Osteoarthritis Outcome Score (KOOS), Tegner activity score, Brittberg score, Noyes sports activity rating scale, and visual analog scale (VAS) for pain as well as 3-T magnetic resonance imaging (MRI) using the magnetic resonance observation of cartilage repair tissue (MOCART) score and functional evaluation by the limb symmetry index (LSI) formed the basis of this study. The Friedman test and the Wilcoxon signed-rank test were performed for a comparison between all time points and 2 separate time points, respectively. If significant differences were revealed, a Bonferroni adjustment to the α level was applied so that P values <.007 (<.05/7) were regarded as significant in the paired comparisons. Results: Significant improvements (P < .05) from baseline to 120 months postoperatively were observed for the IKDC score (mean, 44.1 ± 26.9 to 59.0 ± 27.4), Noyes sports activity rating score (mean, 37.7 ± 30.1 to 62.1 ± 31.3), and KOOS Quality of Life and Pain subscores, whereas no statistically significant improvement was detected for the Brittberg score, Tegner activity score, or VAS score. After 5 years, a slight downward tendency of all clinical scores was evident. After 10 years, the mean MOCART score was 70.4 ± 16.1. Complete filling of the defect was observed in 73.9% of cases, and osteophytes were present in 78.3%. In 65.2% of the cases, a subchondral bone edema <1 cm was visible, whereas in 21.7% of the cases, a subchondral bone edema >1 cm was seen. The mean LSI for the single-legged hop test was 95.6% ± 16.2% and for the triple hop test for distance was 91.3% ± 12.2%. The mean VAS score for self-perceived stability was 60.2 ± 3.5 (range, 0-9.5) for the injured and 60.7 ± 3.8 (range, 0-10) for the uninjured leg. No adhesions or effusions were seen regarding the clinical and radiological outcomes. Conclusion: The significantly improved results on 3 outcome measures after 10 years suggest that MACT represents a suitable option in the treatment of local cartilage defects in the knee.

The management of bite wounds in children—A retrospective analysis at a level I trauma centre

INTRODUCTION Animal bite wounds are a significant problem, which have caused several preventable child deaths in clinical practice in the past. The majority of bite wounds is caused by dogs and cats, and also humans have to be considered to lead to those extreme complicated diagnosis in the paediatric patient population. Early estimation of infection risk, adequate antibiotic therapy and, if indicated, surgical treatment, are cornerstones of successful cures of bite wounds. However, antibiotic prophylaxis and wound management are discussed controversially in the current literature. In our study, we retrospectively investigated the bite source, infection risk and treatment options of paediatric bite wounds. METHODS A total of 1592 paediatric trauma patients were analysed over a period of 19 years in this retrospective study at a level I trauma centre, Department of Trauma Surgery, Medical University of Vienna, Austria. Data for this study were obtained from our electronic patient records and follow-up visits. In our database, all paediatric patients triaged to our major urban trauma centre have been entered retrospectively. RESULTS During the 19-year study period, 1592 paediatric trauma patients met the inclusion criteria. The mean age was 7.7 years (range 0-18.9), 878 (55.2%) were males and 714 (44.8%) were females. In our study population, a total of 698 dog bites (43.8%), 694 human bites (43.6%), 138 other bites (8.7%) and 62 cat bites (3.9%) have been observed. A total of 171 wounds (10.7%) have been infected. Surgical intervention was done in 27 wounds (1.7%). CONCLUSION Gender-related incidence in bite wounds for dog and cat could be detected. Second, our findings for originator of bite wounds reflect the findings in the published literature. Total infection rate reached 10.7%, primary antibiotic therapy was administered in 221 cases (13.9%) and secondary antibiotic therapy in 20 (1.3%) cases. Observed infection rate of punctured wounds and wounds greater than 3 cm was 3 times higher than for all other wounds. Our findings need to be proven in further prospective clinical trials.

Bone graft harvesting using the RIA (reaming irrigation aspirator) system - a quantitative assessment.

ZusammenfassungHINTERGRUND: Die autologe Knochenmarksentnahme gilt noch immer als Goldstandard für die Behandlung von Pseudarthrosen. Mit der intramedullären Knochenmarksentnahme steht eine Alternative zu bisher verwendeten Verfahren wie der Beckenkammentnahme oder der Implantierung von synthetischen Materialien für die Behandlung von Knochendefekten zur Verfügung. Das RIA System, welches mit Bohr und Saugvorrichtung übersetzt werden kann, ist ein System welches den intramedullären Druck senkt und so das Risiko einer Fettembolie deutlich reduziert. Das Ziel der vorliegenden Studie ist die Quantifizierung des gewonnenen intramedullären Knochenmarkes und der Vergleich zu bereits publizierten Daten für die Beckenkammentnahme. METHODE: Acht Leichen (7 männlich, 1 weiblich, 16 Extremitäten) mit einem durchschnittlichen Alter von 68 Jahren (49 bis 79) wurden für die vorliegende Studie verwendet. Die Markraumbohrung wurde in allen acht Leichen mit zwei verschiedenen Bohrköpfen der Stärke 12 und 14 mm durchgeführt. Über einen parapatellaren medialen Zugang, wurde die Tibia antegrad und das Femur retrograd aufgebohrt. ERGEBNISSE: Eine signifikant größere Menge an intramedullärem Knochenmaterial (27 ± 12 g) wurde aus dem Femur im Vergleich zu (17 ± 9 g) aus der Tibia gewonnen (p = 0,007). Es konnte keine signifikante Korrelation mit Alter, Geschlecht, Körpergewicht, Knochenlänge oder BMI erzielt werden. KONKLUSION: Unter Betrachtung unseres Ergebnisses, stellt das RIA System eine innovative Technik zur Knochenmarksgewinnung für Rekonstruktionen der unteren Extremität dar. Eine signifikant größere Menge an Knochenmark wurde aus dem Femur im Vergleich zur Tibia gewonnen (p = 0,007). Eine signifikante Korrelation mit Alter, Geschlecht, Körpergewicht, Knochenlänge oder BMI konnte nicht erzielt werden. Mit unserer Studie konnte nachgewiesen werden, dass mit dem RIA-System eine ausreichende Menge an intramedullärem Knochenmark gewonnen werden kann.SummaryINTRODUCTION: Autologous bone graft is still considered to be the gold standard for treating non-unions in trauma and orthopedic surgery. Intramedullary bone graft harvest appears to be an alternative to other bone graft options such as iliac crest bone graft and synthetic bone substitutes. A one-step reamer-irrigator-aspirator (RIA) system has been developed to reduce the intramedullary pressure and, as a consequence, minimize the risk of fat embolization. The purpose of this study was to determine whether the quantity of harvested intramedullary bone graft is comparable to the quantity of graft that was harvested from the iliac crest in other studies. The aim of the present study was to quantify harvested bone marrow and to compare our results to already published data. METHODS: Eight human cadavers (7 males, 1 female, and 16 limbs) with an average age of 68 years (range, 49–79 years) were obtained for this study. Intramedullary reaming was performed in the tibiae and femora of each cadaver. Two different sizes (12- and 14-mm diameter) of the RIA system were used. After a medial parapatellar incision was made at the knee, antegrade and retrograde reaming were performed in the tibiae and femur to harvest bone graft. RESULTS: A significantly greater quantity of bone graft was harvested from the femora (27 ± 12 g) than the tibiae (17 ± 9 g) (p = 0.007). CONCLUSIONS: On the basis of our present results, harvesting intramedullary bone graft with the RIA system appears to be an innovative technique for bone grafting in limb reconstruction. A significantly greater quantity of bone graft was harvested from the femora than the tibiae (p = 0.007). No significant differences among age, sex, body weight, bone length, or BMI were observed. Our results showed that a sufficient quantity in weight of autogenous bone graft could be obtained using the RIA system.

Incidence and analysis of radial head and neck fractures

AIM To investigate several complications like persistent radial head dislocation, forearm deformity, elbow stiffness and nerve palsies, associated with radial head fractures. METHODS This study reviewed the clinical records and trauma database of this level I Trauma Center and identified all patients with fractures of the radial head and neck who where admitted between 2000 and 2010. An analysis of clinical records revealed 1047 patients suffering from fractures of the radial head or neck classified according to Mason. For clinical examination, range of motion, local pain and overall outcome were assessed. RESULTS The incidence of one-sided fractures was 99.2% and for simultaneous bilateral fractures 0.8%. Non-operative treatment was performed in 90.4% (n = 947) of the cases, surgery in 9.6% (n = 100). Bony union was achieved in 99.8% (n = 1045) patients. Full satisfaction was achieved in 59% (n = 615) of the patients. A gender related significant difference (P = 0.035) in Mason type distribution-type III fractures were more prominent in male patients vs type IV fractures in female patients-was observed in our study population. CONCLUSION Mason type I fractures can be treated safe conservatively with good results. In type II to IV surgical intervention is usually considered to be indicated.

The EGF 61A/G polymorphism – a predictive marker for recurrence of liver metastases from colorectal cancer

ZusammenfassungHINTERGRUND: Der epidermale Wachstumsfaktor (EGF) spielt eine bedeutende Rolle in der Tumorentstehung. Variationen in der DNA Sequenz des EGF Gens, können zu einer Erhöhung der EGF Aktivität führen, von der man annimmt, dass sie das Tumorwachstum beeinflusst. Die aktuelle Studie untersucht den Einfluss des EGF 61A/G Polymorphismus auf das Wiederauftreten von Lebermetastasen beim kolorektalen Karzinom nach Operation. METHODE: Der EGF 61A/G Polymorphismus wurde retrospektiv in 268 fortlaufenden Patienten beiderlei Geschlechts bestimmt: 175 (65%) männliche und 93 (35%) weibliche Patienten, welche chirurgisch kurativ mit (R0) bei Lebermetastasen im Rahmen eines kolorektalen Karzinoms behandelt wurden. ERGEBNISSE: Von den 268 Patienten, hatten 81 (30%) die häufigste (Wildtyp) Variante EGF 61 A/A, 137 (51%) waren heterozygot EGF 61 A/G und 50 (19%) waren homozygot EGF 61 G/G. Adjustiert nach Alter, Geschlecht, UICC Staging und Tumorlokalisation konnten wir ein 1.6 fach höheres Risiko für das Wiederauftreten von Lebermetastasen (HR: 1,6; 95% CI: 1,0–2,5 p = 0,06) bei EGF 61 G/G Homozygoten verglichen mit Trägern des EGF 61 A Allels feststellen. Dieser Effekt war in jungen Patienten (≤ 65 Jahren), welche ein 2.0-fach höheres Risiko für das neuerliche Auftreten von Lebermetastasen hatten (HR: 2,0; 95% CI: 1,1–3,5 p = 0,021), stärker. Bei Patienten über 65 Jahren konnte kein Effekt nachgewiesen werden. Interessanter Weise konnten wir feststellen, dass männliche Patienten mit EGF G/G ein 1,6 fach höheres Risiko für das Wiederauftreten von Metastasen hatten (HR: 1,6; 95% CI: 1,0–2,5 p = 0,07). Eine signifikante Korrelation (p = 0,033) zwischen der Dukes Klassifikation und homozygot EGF 61 G/G konnte ebenfalls festgestellt werden. KONKLUSION: Mit unseren Ergebnissen konnten wir zeigen, auch unter Berücksichtigung unserer kleinen Patientenpopulation, dass Träger des EGF 61G/G Genotyps ein höheres Risiko für neuerliche Lebermetastasen haben – eine Vermutung, die allerdings durch weitere Studien bestätigt werden muss.SummaryBACKGROUND: Epidermal growth factor (EGF) plays an important role in tumorigenesis. Variations in the DNA sequence of the gene EGF can lead to alterations in EGF activity, which is suspected to influence tumor progression. This retrospective study aimed to investigate the influence of EGF 61A/G polymorphism on the recurrence of liver metastases after hepatic surgery in patients with colorectal cancer. METHODS: EGF 61A/G polymorphism was determined in 268 consecutive patients (175 [65%] men and 93 [35%] women, mean age 62 ± 10.3 years) who had liver metastases at primary diagnosis and were treated by surgery with curative intent (R0) for liver metastases from colorectal cancer. RESULTS: Overall, 81 of 268 (30%) patients exhibited wild-type EGF 61 A/A, 137 (51%) were heterozygous EGF 61 A/G and 50 (19%) were homozygous EGF 61 G/G. After adjusting for age, sex, UICC stage and tumor location, we observed a trend-wise 1.6-fold increased risk for hepatic recurrence (HR 1.6; 95% CI 1.0–2.5, P = 0.06) in individuals with the G/G genotype compared with carriers of the A-allele. The effect was much more pronounced in younger patients (≤ 65 years), who showed a 2.0-fold increased risk of hepatic recurrence (HR 2.0; 95% CI 1.1–3.5, P = 0.021). No effect was observed in older patients (≥ 65 years). Interestingly, male patients with EGF G/G had a 1.6-fold higher risk of recurrence (HR 1.6; 95% CI 1.0–2.5, P = 0.07). A significant correlation (P = 0.033) was detected between Dukes classification and the homozygous 61 G/G genotype. CONCLUSION: Despite the limitations of our study, the retrospective results indicate that carriers of the EGF polymorphism might be at higher risk of developing liver recurrences. If confirmed in subsequent studies, genotyping for the EGF A/G variant might help in identification of patients at high risk of recurrence of liver metastases.