Pharmacokinetics of ertapenem in colorectal tissue.

BACKGROUND: There are only limited data on tissue kinetics of ertapenem in colorectal tissue more than 3 h after administration of the drug. The purpose of this study was to assess the pharmacokinetics (PK) of ertapenem in colorectal tissue via population PK modeling. PATIENTS AND METHODS: Patients ≥18 years requiring surgical intervention at the colon and/or rectum were eligible (ClinicalTrials.gov identifier: NCT 00535652). Tissue and blood samples were taken during surgery after a single dose of 1 g ertapenem. Ertapenem concentration was determined by high-performance liquid chromatography/mass spectrometry. Population PK modeling was performed in S-ADAPT. RESULTS: Twenty-three patients were enrolled. The highest tissue concentration was 6.4 ± 2.3 mg/kg, the highest total plasma concentration 51.34 ± 9.4 mg/l, the highest unbound plasma concentration 7.05 ± 1.1 mg/l, and the unbound fraction in plasma was 14-15% for total ertapenem concentrations below approximately 22 mg/l, 19% at 100 mg/l, and 25% at 250 mg/l. The estimated geometric mean terminal half-life was 2.5 h for plasma and tissue. In the Monte Carlo simulation, a single dose of 1,000 mg ertapenem achieved robust (≥90%) probabilities of target attainment up to a minimum inhibitory concentration (MIC) of approximately 2 mg/l for the bacteriostasis target (free time above MIC, fT(>)(MIC) = 20%) and up to 0.25-0.5 mg/l for the near-maximal killing target (40% fT(>)(MIC)). CONCLUSION: Our data indicate an adequate penetration of ertapenem into uninfected colorectal tissue up to 8.5 h (35% of the dosing interval) after administration of 1 g intravenously.

[Indications for surgical resection of benign pancreatic tumors]. / Indikationen zur chirurgischen Therapie benigner Pankreastumoren.

Benign pancreatic tumors should undergo surgical resection when they are symptomatic or--in the case of incidental discovery--bear malignant potential. This is the case for the majority of benign pancreatic tumors, especially for intraductal papillary mucinous neoplasms or mucinous cystic adenomas. In addition, resection is indicated for all tumors where preoperative diagnostic fails to provide an exact classification.Several different operative techniques are available. The treatment of choice depends on the localization of the tumor, its size and on whether there is evidence of malignant transformation. Partial duodenopancreatectomy is the oncological treatment of choice for tumors of the pancreatic head whereas for tumors of the pancreatic tail a left-sided pancreatectomy is appropriate. Middle pancreatectomy or duodenum-preserving resection of the pancreatic head is not a radical oncologic procedure. They should only be performed in cases of tumors without malignant potential.

Intraabdominal tissue concentration of ertapenem.

OBJECTIVES: Ertapenem, a class I carbapenem, is approved for the treatment of mild to severe intraabdominal infections, but its in vivo concentrations in intraabdominal tissues are unknown. The purpose of this study was to determine the concentration of ertapenem in intraabdominal tissue. PATIENTS AND METHODS: After informed consent 48 patients, 23 female and 25 male with a median age of 58 years (34-81), requiring surgical intervention at intraabdominal organs were enrolled. Patients received 1 g of ertapenem intravenously for perioperative prophylaxis. Tissue samples were taken after resection of parts of the organs. Plasma samples were taken when tissue samples were taken. Drug concentrations were determined by liquid chromatography/mass spectrometry. An ANCOVA test (analysis of covariance) was performed to assess organ-specific differences in ertapenem concentration and penetration ratios. RESULTS: Mean+/-SD ertapenem tissue concentration (mg/kg) was 16.0+/-8.8 in the gall bladder, 12.1+/-5.3 in the colon, 7.0+/-5.7 in the small bowel, 4.5+/-2.3 in the liver and 3.4+/-2.9 in the pancreas. The mean tissue/plasma ratio was 0.19 (colon), 0.17 (small bowel), 0.17 (gall bladder), 0.088 (liver) and 0.095 (pancreas). The ANCOVA test revealed statistically significant organ-specific differences in ertapenem tissue concentration in the gall bladder versus liver/pancreas and in tissue penetration for the colon versus liver/pancreas. CONCLUSIONS: These pharmacokinetic results support the assumption that ertapenem is suitable for the treatment of intraabdominal infections.

Antibiotic prophylaxis in severe acute pancreatitis.

Severe acute pancreatitis is considered to be a subgroup of acute pancreatitis with the development of local and/or systemic complications. A significant correlation exists between the development of pancreatic necrosis, the frequency of bacterial contamination of necrosis and the evolution of systemic complications. Bacterial infection and the extent of necrosis are determinants for the outcome of severe acute pancreatitis. The late course of necrotizing pancreatitis is determined by bacterial infection of pancreatic and peripancreatic necroses. Mortality increases from 5-25% in patients with sterile necrosis to 15-28% when infection has occurred. The use of prophylactic antibiotics has been recommended in patients with necrotizing pancreatitis. Several controlled clinical trials demonstrated a significant reduction in pancreatic infections or a significant reduction of hospital mortality. However, the results of these clinical trials are controversial and not convincing. Recently, the largest randomized placebo-controlled, double-blind trial has been able to demonstrate that antibiotic prophylaxis with ciprofloxacin and metronidazole has no beneficial effects with regard to the reduction of pancreatic infection and the decrease of hospital mortality. The clinical data from this placebo-controlled trial do not support antibiotic prophylaxis in all patients with necrotizing pancreatitis, but in specific subgroups of patients with pancreatic necrosis and a complicated course.

[Possibilities in improving patients's turn-over coordination in the OR of an University Hospital]. / Möglichkeiten zur Ablaufoptimierung im OP - Prozessanalyse der Wechselzeiten in einem OP der Maximalversorgung.

An efficient Operating Room (OR) management might increase the cost-effectiveness of an OR. For this purpose, we have evaluated the coordination and the times of the solitary processes that are involved in the patient turnover. The mean time between skin suture of the preceding patient and incision of the following patient (SI-time) was, depending on the type of operation, between 44 and 78 minutes. Mean empty-room time (ERT) was 7 minutes. SI-times depended on various factors, including the times necessary to discharge the preceding patient from the OR and the times necessary for induction of anesthesia or for preparation of the OR. Altogether, our data provide evidence for the fact, that optimisation of the patients turnover can decrease SI-times between 10-15 minutes. Although this period appears too short to reliably allow an additional scheduled operation during regular working hours, an improved coordination may result in reduced overtimes of the OR-staff and thus should increase staff satisfaction.

[The balanced scorecard. "Tool or toy" in hospitals]. / Balanced Scorecard. "Tool or toy" im Krankenhaus?

The change in hospital funding with diagnosis related groups (DRG), medical advances as well as demographic changes will call for new quantitative and qualitative standards imposed on German hospitals. Increasing costs and competition in the health care sector requires new and innovative strategies for resource management. Today's policy is mainly defined by rationing and intensified workload. The introduction of DRGs will presumably further constrict management perspectives on pure financial aspects. However, to ensure future development, compassionate services and continued existence of hospitals, a balance of seemingly conflicting perspectives, such as finance, customer, process, learning and growth are of utmost importance. Herein doctors and nurses in leading positions should play a key role in changing management practice. For several years the balanced scorecard has been successfully used as a strategic management concept in non-profit organizations, even in the health care sector. This concept complies with the multidimensional purposes of hospitals and focuses on policy deployment. Finally it gives the opportunity to involve all employees in the original development, communication and execution of a balanced scorecard approach.

[OR-manager: surgeon or anaesthetist?]. / OP-Management: "Chirurg oder Anästhesist?". Eine interdisziplinäre Herausforderung.

The heart of any surgical department is the operating room (OR) area. Any disturbances in the daily routine will affect the work flow of the whole hospital. On account of its central function, with numerous connections to other departments, the OR is the crystallisation point for deficiencies in various events and processes. As an example, the major complaints made by a surgical department regarding workflow and communication are outlined. To solve these problems, an "OR organization" team was established, which worked on the basis of a newly developed OR statute. Within 1 year the employees were more contentment and the workflow had improved. However, even in the second year of central OR management there is still the need to further stabilize the system as mismanagement still occurs.

Interaction of fibronectin and aggregation substance promotes adherence of Enterococcus faecalis to human colon.

This in vitro study investigates the interaction between aggregation substance (AS), a virulence factor of Enterococcus faecalis, and colonic mucosal fibronectin in normal colon and colon from patients with Crohn's disease. Fibronectin was found to be overexpressed in Crohn's disease compared to normal colon. Compared to E. faecalis OG1X:pAM944 (AS-negative), E. faecalis OG1X:pAM721 (expressing AS) showed a significantly enhanced adhesion to human colonic mucosa in normal colon and in colon from patients with Crohn's disease. Double-staining of fibronectin and AS-positive enterococci showed that colocalization of bacteria and fibronectin was significantly more frequent in Crohn's disease than in normal colon. Preincubation of bacteria with soluble fibronectin caused a significant reduction in the adherence to fibronectin. In conclusion, the interaction between AS and fibronectin plays is an important factor that mediates adhesion of Enterococcus faecalis to colonic mucosa. This might be one of the mechanisms responsible for bacterial translocation of Enterococcus faecalis.

Efficacy of oral ofloxacin for single-dose perioperative prophylaxis in general surgery--a controlled randomized clinical study.

BACKGROUND: Perioperative antibiotic prophylaxis surely reduces surgical infection rate. Pharmacokinetic data of oral ofloxacin in combination with its antibacterial spectrum suggest effective protection against perioperative infection. In addition, costs, adverse effects, and induction of microbial resistance are low. Therefore we performed a controlled randomized study comparing oral and intravenous single dose prophylaxis. METHODS: A total of 61 patients undergoing colonic or pancreatic resection randomly received either a single dose standard intravenous prophylaxis or ofloxacin 400 mg and metronidazole 500 mg orally 2 h before surgery. Postoperative infections were recorded for 3 weeks. RESULTS: Groups were very well comparable regarding age, overweight, concomitant disease, type and duration of surgery, blood loss, and volume support. Infectious complications occurred in 14.8% after parenteral and 3.3% after enteral antibiotic prophylaxis. There was no difference in post-operative hospital stay. CONCLUSION: The data demonstrate that single-dose oral ofloxacin is at least as effective as a standard intravenous prophylaxis in patients with colonic or pancreatic resection. It offers significant advantages regarding costs and ease of administration.

Pharmacokinetic basis for oral perioperative prophylaxis with ofloxacin in general surgery.

BACKGROUND: Perioperative prophylaxis is recommended to be administered intravenously which, compared to oral prophylaxis, is more expensive. However, pharmacokinetic data on oral perioperative prophylaxis in patients with preoperative surgical and anesthesiological preparation are not available. PATIENTS AND METHODS: 40 patients with open hernial repair or cholecystectomy (low-risk group), colonic or pancreatic resection (high-risk group) received a standard single-dose perioperative prophylaxis with 4.5 g mezlocillin and 0.5 g metronidazole intravenously in addition to 400 mg ofloxacin orally 2 h prior to surgery. Antibiotic concentrations were measured perioperatively and pharmacokinetic data calculated. RESULTS: Serum and tissue concentrations of ofloxacin were above the MIC90 of the potential bacterial spectrum for surgical infection throughout the entire operation. Pharmacokinetic data were not influenced by preoperative surgical or anesthesiological preparation. CONCLUSION: Tissue and serum concentrations and the antibacterial spectrum of orally administered ofloxacin suggest effective protection against perioperative infection. Pharmacokinetic data confirm that oral ofloxacin may be used effectively as single-dose perioperative antibiotic prophylaxis. Since there are no clinical data comparing oral and intravenous singLe-dose prophylaxis, a prospective randomized clinical trial should be performed.

Prevention of severe change in acute pancreatitis: prediction and prevention.

Bacterial infection of pancreatic necrosis is the most frequent local complication of severe acute pancreatitis and is responsible for the majority of deaths in this disease. The development of systemic complications of severe acute pancreatitis such as septic multiple organ failure is closely related to infected necrosis. In this review, the factors predisposing to a severe course of acute pancreatitis are discussed as are clinical and laboratory markers which allow identification of patients at risk. Prevention of complications of acute pancreatitis is difficult. A variety of drugs including antiproteases and antiinflammatory agents have been shown to be of no benefit with regard to the reduction of severe complications. At present, based on the results of controlled trials, there is the widespread belief that prophylactic antibiotics are capable of reducing the incidence of infected pancreatic necrosis. New approaches for the prevention of systemic complications of severe acute pancreatitis are total enteral nutrition and local arterial infusion of antibiotics and antiproteases into the celiac trunk.

Early severe acute pancreatitis: characteristics of a new subgroup.

This study focuses on patients with severe acute pancreatitis complicated by organ failure within the initial phase of the disease. Data of 158 patients with severe acute pancreatitis (SAP) admitted to hospital within 72 hours after onset of symptoms were prospectively documented and analyzed for the occurrence of early severe acute pancreatitis (ESAP). ESAP was defined as presence of organ failure (OF) at admission. Forty-seven (30%) patients had ESAP, compared with 111 patients without OF (SAP group). In a multivariate analysis, the main factor predisposing to ESAP was the presence of extended pancreatic necrosis (odds ratio, 3.8), whereas biliary pancreatitis was associated with a slightly lower risk compared with alcoholic pancreatitis (odds ratio, 0.34). Compared with SAP, patients with ESAP more frequently developed intractable organ failure, which posed the indication for surgical treatment. Surgical necrosectomy due to progressive OF had to be performed in 89% of the ESAP patients and in 60% of the SAP patients. The incidence of infected pancreatic necrosis did not differ between both groups (23 vs. 21%). Mortality was significantly higher in ESAP (42 vs. 14%; p = 0.0003). ESAP is characterized by the presence of extended pancreatic necrosis and a complicated clinical course. Intractable organ failure is a frequent finding. Given the poor prognosis of ESAP, these patients should be treated in specialized intensive care units.

[Infected necroses and pancreatic abscess: surgical therapy]. / Infizierte Nekrosen und Pankreasabszess: Operative Therapie.

Infected pancreatic necrosis and pancreatic abscesses are severe complications of necrotizing pancreatitis. Compared to infected necrosis, pancreatic abscess is associated with lower mortality. Surgical treatment is the current standard. Necrosectomy is performed as a single-step operation in combination with postoperative drainage/lavage or as scheduled reoperation. In selected cases, pancreatic abscesses can be successfully drained by percutaneous interventional drainage. Mortality in infected necrosis is 20-30% and 5-10% in patients with pancreatic abscess.

Management of patients with extended pancreatic necrosis.

BACKGROUND: Extended pancreatic necrosis pose a considerable therapeutic problem in patients with necrotizing pancreatitis. AIM: Factors that limit conservative treatment in patients with extended pancreatic necrosis were analyzed. METHODS: The clinical course of 61 patients with an extent of necrosis of more than 50% of the gland (according to contrast-enhanced CT scan) were analysed with special regard to systemic complications. Indications for surgical treatment were either persistent organ failure or pancreatic infection. RESULTS: 10 patients were managed by conservative treatment, 51 (84%) patients underwent operation. Indications for surgery were sepsis with or without organ failure in 17 patients, persistent organ failure in another 17 patients, persistent SIRS in 13 patients and local complications in 4 patients. Pancreatic infection was present in 25 patients. The incidence of systemic complications did not differ between infected and sterile necrosis, but they occurred earlier in sterile necrosis. CONCLUSIONS: Persistent organ failure is limiting conservative treatment during the early course in patients with sterile necrosis. The latter course is characterized by a high incidence of pancreatic infection and septic organ failure.

[Stenting in chronic pancreatitis--the mistakes and limitations]. / Stenting bei chronischer Pankreatitis--Fehler und Limitationen.

Endoscopic treatment of chronic pancreatitis using pancreatic duct stents was first described 15 years ago. Considering our own experience and the data of the literature we describe indications, contraindications, risks and limitations of the procedure and on the other hand its therapeutic effects. According to the actual experience an indication for pancreatic duct stenting can be seen in patients with a solitary prepapillary stenosis without stenosis of side branches or as success control for a planned surgical intervention. Contraindications are suspected malignancy, multiple pancreatic duct stenosis in the main duct or stenosis in small ducts and chronic calcifying pancreatitis with pancreatic duct stones. From 6/92 until 5/97 189 patients were operated for chronic pancreatitis in the Ulm University Hospital. Of these patients 35 (18.7%) were unsuccessfully treated preoperatively in other hospitals by pancreatic duct stent. Because of frequent complications like stent dislocation and stent occlusion repeated ERCPs (4.5/patient) and stent exchanges (3.7/patient) were performed. A therapeutical long-term benefit of pancreatic duct stenting is questionable, a definitive therapy can only be achieved in a small group of patients. However stent-induced changes of the pancreatic duct similar to chronic pancreatitis can be observed in up to 80% of all patients. Long-term observations of the reversibility of these stent-induced changes are missing, persisting chronic pancreatitis in the stented region is reported in animal models and in humans. The rates in the literature for stent dislocation and stent occlusion rate are 10-18% and 39-100% respectively. Induction of acute pancreatitis (up to 10%), duodenal reflux into the pancreatic duct, and bacterial infection with abscess formation are further severe and frequent complications of pancreatic duct stenting (1, 2). Lethal courses are reported (3, 4). Endoscopic pancreatic duct stenting in chronic pancreatitis at present is not indicated because of low success rate and a substantial risk of complications.

[Necrosectomy or anatomically guided resection in acute pancreatitis]. / Nekrosektomie oder anatomiegerechte Resektion bei akuter Pankreatitis.

Necrotizing pancreatitis is still associated with considerable morbidity and mortality. Formerly, surgical treatment with early and extensive pancreatic resection has been the standard. Improvements in our understanding of the pathogenesis of the disease and progress in the field of intensive care therapy have made conservative therapy the initial standard in the treatment of necrotizing pancreatitis. A considerable percentage of patients with sterile necrosis can be managed with low morbidity and mortality by conservative treatment without operation. Nevertheless, surgical treatment is indicated in patients with infected necrosis and in sterile necrosis if multiorgan failure persists over a limited period of time despite maximum intensive care therapy. Pancreatic resection should be abandoned for surgical treatment of pancreatic necrosis, as results with regard to morbidity, mortality and long-term outcome are unsatisfactory. Today the surgical standard is careful digital necrosectomy, which must be followed by either postoperatve drainage, repeated open lavage or continuous closed lavage. In experienced hands, all three procedures provide similar results with regard to morbidity and mortality.

Aggregation substance promotes colonic mucosal invasion of Enterococcus faecalis in an ex vivo model.

BACKGROUND: Bacterial translocation through the gastrointestinal tract is the crucial step in the pathogenesis of intraabdominal infections. We assessed whether aggregation substance (AS), a bacterial adhesin and virulence factor of Enterococcus faecalis, promotes bacterial translocation and colonic mucosal invasion in an ex vivo experiment. METHODS: Colonic mucosa of male Wistar rats was placed in a modified Ussing system. The mucosal side of the chamber was filled with a suspension of E. faecalis OG1X:pAM721 (AS-positive) or E. faecalis OG1X (AS-negative). The serosal side was filled with sterile Dulbecco's modified Eagle's medium. For assessment of colonic mucosal invasion the mucosal side was incubated for 2.5 h with a suspension of AS-positive or AS-negative enterococci. After being washed, a solution of gentamicin and penicillin G in tissue culture medium was added on both sides in order to kill extracellular bacteria. Subsequently, the mucosa was removed from the system, washed, lysed with Triton X-100, and homogenized. Viable intramural bacteria were quantified by plating serial dilutions of the homogenate on Todd-Hewitt broth agar plates. To quantify bacterial translocation samples which were taken at various time points from the serosal side were plated on Todd-Hewitt broth agar plates and colony forming units (CFU) were determined. RESULTS: Invasion of the AS-positive E. faecalis strain OG1X:pAM721 into the colonic mucosa was significantly higher than invasion rates of the AS-negative strain OG1X (2.88 log(10) CFU/ml vs 1.73 log(10) CFU/ml; P = 0.02). However, none of the tested strains was found to translocate from the mucosal to the serosal side within the incubation time of 4 h. CONCLUSIONS: The aggregation substance promotes invasion of E. faecalis into colonic mucosa.