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.

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.

The risk of pancreaticointestinal anastomosis can be predicted preoperatively.

The risk of developing postoperative complications following pancreatic resection depends mainly on how difficult it is to perform a proper pancreaticointestinal anastomosis. We have evaluated the serum pancreolauryl test, a rapid tubeless pancreatic function test, as a simple preoperative predictor of the degree of pancreatic fibrosis. Degree of fibrosis in turn provides an indirect parameter for the difficulties of performing a proper and safe pancreaticointestinal anastomosis. In 35 patients (21 chronic pancreatitis, 14 pancreatic tumors) undergoing major pancreatic resection, we found a negative correlation (r = -0.75, p < 0.001) between the degree of fibrosis at the resection margin and the serum pancreolauryl test results. Patients with chronic pancreatitis had a significantly higher degree of fibrosis at the resection margin (59 +/- 22 vs. 34 +/- 25%; X +/- SD; p < 0.01) and lower fluorescein serum concentrations (2.6 +/- 1.9 vs. 4.3 +/- 2.1 micrograms/ml; X +/- SD; p < 0.01) in comparison with patients with pancreatic tumors. These findings indicate that the degree of pancreatic fibrosis, the difficulties of performing a proper pancreaticointestinal anastomosis, and subsequently the potential risk of postoperative complications can easily be predicted preoperatively.

Influence of etiology on the course and outcome of acute pancreatitis.

It has been supposed that there are differences with regard to clinical course and outcome due to the underlying etiological factor in acute pancreatitis. Therefore, the objective of this study was to analyze the severity of the disease, serum enzymes, indicators of necrosis, systemic complications, and mortality in acute pancreatitis with regard to the etiology. One hundred ninety patients with acute pancreatitis (127 male, 63 female) were studied prospectively and subdivided into three etiological groups: (i) alcohol, (ii) gallstones, and (iii) other causes and idiopathic acute pancreatitis. Severity scores (Ranson and Bank) and findings by contrast-enhanced computed tomography were similar in all three groups. Analysis of serum enzymes [lipase, aspartate aminotransferase (ASAT)] and indicators of necrosis (C-reactive protein, alpha 1-antitrypsin, alpha 2-macroglobulin, and lactate dehydrogenase) showed only for ASAT within 24 h significantly higher levels in biliary acute pancreatitis in comparison with the other groups. There were no differences in the rate of infected pancreatic necrosis and mortality in alcohol-related acute pancreatitis (31 and 5.3%), biliary acute pancreatitis (38 and 10%) and acute pancreatitis due to other etiological factors (43 and 5.5%). In conclusion, this study clearly showed that once the pathogenetic mechanisms have initiated the disease, the course and outcome of acute pancreatitis are not influenced by the underlying etiological factor.

Pancreatic necrosis: an early finding in severe acute pancreatitis.

Despite the clinical importance of pancreatic necrosis in the course of acute pancreatitis, little is known about when it develops. Serum C-reactive protein (CRP) is a reliable parameter with a high deduction rate for pancreatic necrosis. We analyzed 199 patients with acute pancreatitis. The development of pancreatic necrosis was ascertained by a daily measurement of serum CRP in 45 patients with contrast-enhanced computed tomographic-proven necrotizing pancreatitis. In all 45 cases, the criteria for pancreatic necrosis were satisfied within the first 4 days of the onset of symptoms. This indicates that pancreatic necrosis is an early finding that develops within hours.

Surgical management of necrotizing pancreatitis.

In necrotizing pancreatitis, surgical treatment is indicated in patients with infected necrosis. Conservative management should be favored if necrosis remains sterile and the patient responds to intensive care therapy. Different surgical techniques have been established during the past years, including conventional drainage, open and semiopen drainage, and closed management with postoperative continuous lavage of the lesser sac. For experienced physicians, these techniques provide comparable results, and none has been proved to be superior to the others.

[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.

[Prognosis in pancreatic carcinoma]. / Die Prognose des Pankreaskarzinoms.

Pancreatic cancer is one of the most frequent carcinomas of the human gastrointestinal tract. despite considerable progress in diagnosis, its prognosis has remained unchanged during the last years. Up to now, there is no possibility to screen patients for pancreatic carcinomas, and the symptoms of the disease are uncharacteristic and often misleading. Surgical treatment, with resection of the tumor is the only chance for cure, but for experienced pancreatic surgeons, an advanced tumor stage at the time of operation is a common finding. Large studies reveal the poor prognosis of the disease. Only 20-30% of all patients suffering from pancreatic cancer can be operated with curative intention. In 80-85% of all cases, the tumor has spread into peripancreatic lymph nodes. Thus, mean 5-years survival rates of 3 to 5% are commonly reported, and the median survival time after establishment of diagnosis is 4-6 months. Improvements in surgical technique and postoperative patient's care have led to an impressive decrease in the formerly considerable morbidity and mortality after pancreatic resection. If the tumor can be resected at an early stage and the regional lymph nodes are not involved, median 5-years survival rates of 20-40% are commonly reported. Further approaches include more radical surgical procedures with dissection of the entire peripancreatic region and resection of the upper abdominal blood vessels. Whether this new technique or a combination of operation, radiation and chemotherapy will improve the prognosis of the disease remains unclear. Large clinical trials are necessary to prove these assumptions.

[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.

Natural history of acute pancreatitis and the role of infection.

Bacterial infection of pancreatic necrotic tissue is a frequent complication of severe acute pancreatitis. Infected pancreatic necrotic tissue is observed in 30-70% of all patients suffering from necrotizing pancreatitis. It is the leading cause of deaths in severe acute pancreatitis, with mortality rates ranging from 15 to 30%. The incidence of infection increases with the extent of the necrotic areas and with the time after onset of pancreatitis. Compared to patients with sterile necrosis, those with infection of the necrotic areas have an increased mortality, and systemic complications occur more frequently. Standard treatment for infected pancreatic necrotic tissue is surgical debridement, whereas conservative management is feasible in approximately 30% of the patients with sterile necrosis. As bacterial infection of pancreatic necrotic tissue has a tremendous impact on the prognosis of the disease and on the patient's clinical course, efforts have been made to prevent it. Although clinical and experimental data provide evidence that prophylactic antibiotics have beneficial effects on the outcome and course of patients with severe acute pancreatitis, this topic has to be investigated further. General recommendations concerning the early use of antibiotics have to await the results of larger, double-blind studies.

[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.

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.

[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.

[Antibiotic use in necrotizing pancreatitis. Results of a controlled study]. / Antibiotika bei nekrotisierender Pankreatitis. Ergebnisse einer kontrollierten Studie.

BACKGROUND AND OBJECTIVE: The clinical course and death rate in acute necrotizing pancreatitis (ANP) are largely determined by septic complications as part of bacterial invasion of the necrotic tissues. It remains unclear whether antibiotic prophylaxis reduces bacterial invasion of the necroses or septic complications. It was, therefore, the aim of this study to evaluate the effect of prophylactic administration of antibiotics to patients with ANP. PATIENTS AND METHODS: In a prospective randomized study 13 patients with ANP and sterile necroses (quantified by contrast-enhanced computed tomography) were given twice daily 200 mg ofloxacin and twice daily 500 mg metronidazole intravenously. The results were compared to those in a control group of patients with ANP (n = 13) who had not initially received antibiotics. In both patient groups fine-needle biopsies of the necrotic areas were performed on days 1, 3, 5, 7 and 10. If there was evidence of infection, antibiotics were then also given to patients of the control group. RESULTS: The extent of the necroses was the same, 40%, in both groups. These necroses became infected in a median of 9.5 (treated group) and 10 days (untreated group). The clinical course, documented by the APACHE II score, showed significant improvement under antibiotic treatment (days 1-5-10: scores 15-13.0-9.5). In the (initially untreated) control group the clinical condition deteriorated significantly (days 1-5-10: score 11.5-15.0-16.0). The changes from days 1 to 5, 5 to 10 and 1 to 10 were highly significant (Wilcoxon test, P < 0.01). None of the patients in the antibiotic group died within the first 3 weeks, but 2 of the 13 in the control group died. CONCLUSION: Antibiotic prophylaxis neither prevented nor delayed bacterial infection of the necrotic pancreas. But it significantly improved the clinical course if started before the onset of infection of the pancreatic necroses.

[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.

Infections complicating pancreatitis: diagnosing, treating, preventing.

The most important risk factor in patients suffering from acute necrotizing pancreatitis is pancreatic infection, a factor that determines the course of the disease, its therapeutic management, and its outcome. The bacterial infection route is very likely via the colon. In patients with acute pancreatitis, the infection rate is about 40 to 70% within the first 3 wks. Bacteria most frequently found are those from the gastrointestinal tract: Escherichia coli, Pseudomonas species, Streptococcus fecalis, Enterococcus, and Staphylococcus aureus. Screening methods for infected necrotizing pancreatitis include fine needle puncture by ultrasonography or computed tomographic guidance with Gram staining and culture of the aspirate. We previously investigated different broad-spectrum antibiotics with regard to their efficacy at preventing infection. This analysis indicated that antibiotics have different efficacy factors based on pharmacodynamic properties. Imipenem and quinolones, in combination with metronidazole, are the drugs of choice for treating or preventing pancreatic infection, whereas aminoglycosides do not enter the pancreas and therefore are not indicated. Based on increasing evidence that patients with acute necrotizing pancreatitis will benefit by early and appropriate antibiotic therapy, we altered the approach in such patients with an immediate start of antibiotic therapy continued for at least 14 days. We have found a reduction of the infection rate to 33% (11/32) in the third week after the onset of the disease. This treatment of the infection and the possibility of delaying operative intervention resulted in optimal surgical conditions. However, further prospective, controlled, and randomized studies are necessary to determine which antibiotics and antimycotic therapeutic regimens should be chosen.

Bacterial infection and extent of necrosis are determinants of organ failure in patients with acute necrotizing pancreatitis.

BACKGROUND: The risk factors predisposing to organ failure in patients with necrotizing pancreatitis remain unclear. The relationship between the extent of pancreatic necrosis, the presence of infection and the incidence of organ failure was analysed. METHODS: In a retrospective review, the occurrence of pulmonary insufficiency, renal insufficiency, shock, sepsis/sepsis-like syndrome (SLS) and coagulopathy was evaluated in 273 patients with necrotizing pancreatitis, and a comparison was made between patients with sterile or infected necrosis. Additionally, the relation between the incidence of organ failure and extent of pancreatic parenchymal necrosis was investigated by classifying the patients into three groups according to the amount of necrotic tissue found by contrast-enhanced computed tomography (group 1, extent less than 30 per cent; group 2, 30-50 per cent; group 3, more than 50 per cent). RESULTS: Organ failure was more frequent in patients with infected necrosis than in those with sterile necrosis. Differences were found in the incidence of pulmonary insufficiency, sepsis/SLS and coagulopathy. Organ failure occurred more frequently in group 3 than in group 2 or 1 (95 versus 79 and 66 per cent; P = 0.0004). The extent of infected necrosis was not related to the incidence of organ failure (group 1, 88 per cent; group 2, 86 per cent; group 3, 96 per cent). However, there was a relation between the incidence of organ failure and the extent of sterile necrosis (group 1, 59 per cent; group 2, 74 per cent; group 3, 94 per cent; P = 0.0001). Multivariate analysis confirmed the presence of infection and the extent of necrosis as independent determinants of organ failure. CONCLUSION: The incidence of organ failure is determined by both bacterial infection and extent of necrosis. The incidence of organ failure is determined by the extent of necrotic parenchyma in patients with sterile necrosis. Infected necrosis is associated with a high incidence of organ failure irrespective of the extent of necrosis.