Mathias Wittau

Systematic review and meta-analysis of antibiotic prophylaxis in severe acute pancreatitis

Abstract Objective. The incidence of acute pancreatitis varies from 5 to 80 per 100,000 throughout the world. The most common cause of death in these patients is infection of pancreatic necrosis by enteric bacteria, spurring the discussion of whether or not prophylactic antibiotic administration could be a beneficial approach. In order to provide evidence of the effect of antibiotic prophylaxis in severe acute pancreatitis (SAP) we performed an updated systematic review and meta-analysis on this topic. Methods. The review of randomized controlled trials was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. We conducted a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. For assessment of the treatment effects we calculated the risk ratios (RRs) for dichotomous data of included studies. Results. Fourteen trials were included with a total of 841 patients. The use of antibiotic prophylaxis was not associated with a statistically significant reduction in mortality (RR 0.74 [95% CI 0.50–1.07]), in the incidence of infected pancreatic necrosis (RR 0.78 [95% CI 0.60–1.02]), in the incidence of non-pancreatic infections (RR 0.70 [95% CI 0.46–1.06]), and in surgical interventions (RR 0.93 [95% CI 0.72–1.20]). Conclusion. In summary, to date there is no evidence that supports the routine use of antibiotic prophylaxis in patients with SAP.

The Role of the Casein Kinase 1 (CK1) Family in Different Signaling Pathways Linked to Cancer Development

The members of the casein kinase 1 (CK1) family are highly conserved and are expressed in many eukaryotes ranging from yeast to humans. Mammalian CK1 isoforms (a, ß, ?, d, e) and their splice variants are involved in diverse cellular processes including membrane trafficking, circadian rhythm, cell cycle progression, chromosome segregation, apoptosis and cellular differentiation. Mutations and deregulation of CK1 expression and activity has been linked to various diseases including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, sleeping disorders and proliferative diseases such as cancer. In this review, we summarize the functions of CK1 and outline the participation of CK1 in signal transduction pathways linked to cancer development.

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery.

ABSTRACT Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m2). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.)

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.

Population Pharmacokinetics and Target Attainment of Ertapenem in Plasma and Tissue Assessed via Microdialysis in Morbidly Obese Patients after Laparoscopic Visceral Surgery

ABSTRACT Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in the plasma, subcutaneous tissue, and peritoneal fluid of morbidly obese patients. Six female patients (body mass index, 43.7 to 55.9 kg/m2) received 1,000 mg ertapenem as 15-min infusions at 0 and 26 h. On day 2, the unbound ertapenem concentrations in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of an unbound ertapenem concentration above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3 liters/h (coefficient of variation, 21.6% for between-patient variability) and the volume of distribution at steady state was 57.8 liters in patients with a 53-kg fat-free mass. The area under the concentration-time curve (AUC) for ertapenem was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid than the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life, <15 min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust (>90%) target attainment probabilities for MICs of up to 1 mg/liter in plasma, 0.25 to 0.5 mg/liter in subcutaneous tissue, and 0.5 mg/liter in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery. (This study has been registered at ClinicalTrials.gov under identifier NCT01407965.)

The Minimal-Access Kidney Transplantation Technique in Living-Donor Transplantation: Results From a Retrospective Analysis

OBJECTIVES During the last 15 years, there was tremendous progress in minimally invasive surgery and minimal-access surgery. Many conventional surgical procedures were replaced by these techniques, resulting in a wide range of benefits for the patients. In kidney transplantation, many centers choose an approach to the iliac fossa through an oblique or J-shaped incision. This might have possible disadvantages due to the extent of tissue trauma. Thus, we introduced a minimal-access kidney transplantation technique (MAKT) as a transplantation method in our center. We retrospectively analyzed this technique used for 11 living-donor kidney transplants and report here our experience. PATIENTS AND METHODS From April 2008 to July 2011, 11 living-donor kidney recipients were subjected to the MAKT and were matched (age, sex) with a historical group from our center from 2000 to 2007. To analyze the assumption of noninferiority of the MAKT in comparison to the standard approach, a matched case-control study design was chosen, with creatinine level at 1 year after transplantation as the primary outcome variable. We used a Wilcoxon signed rank test; 1-sided significance level was 2.5%. RESULTS Eleven recipients were included. Both groups were almost similar regarding age and body mass index. Characteristics of the procedure were significantly different only for cold ischemic time (114 minutes MAKT vs 77 minutes historical group). In the MAKT group, there were no reinterventions necessary, no wound infections, no incisional hernia, no acute rejection episodes, no graft losses, and 2 lymphoceles occurred. Further, no urinary leakage or ureteral stenosis and no vascular complications were observed. The statistical analysis of the primary endpoint revealed a noninferiority of the MAKT technique (P = .0005). CONCLUSIONS Considering the fact that this is an initial series and a retrospective analysis, the applied MAKT technique seems to be safe in terms of both graft function after 1 year and surgical complications.

Management of a giant perineal condylomata acuminata.

A condylomata acuminata infection is caused by human papillomaviridae (HPV). This sexually transmitted condition most often affects the perineal region. Importantly, infections with types 16 and 18 are associated with an increased risk for anal and cervix cancer. In most cases topical therapy is sufficient for successfully treating condylomata acuminata. Here, we report the case of a 51-year old patient who suffered from a giant perianal located condylomata acuminata which had developed over a period of more than 10 years. Imaging by MRI revealed a possible infiltration of the musculus sphincter ani externus. Because a topical treatment or a radiotherapy was considered unfeasible, a surgical treatment was the only therapeutic option in this unusual case. First, a colostomy was performed and subsequently a resection of the tumor in toto with circular resection of the external portion of the musculus sphincter ani externus was performed. The large skin defect was closed by two gluteus flaps. The rectum wall was reinserted in the remnant of the musculus sphincter ani externus. Postoperatively, parts of the flaps developed necrosis. Therefore, a vacuum sealing therapy was initiated. Subsequently, the remaining skin defects were closed by autologous skin transplantation. Six months later the colostomy could be reversed. To date, one year after first surgery, the patient has still a normal sphincter function and no recurrence of the condylomata acuminata. This case report demonstrates how giant condylomata acuminata can be successfully treated by extended surgical procedures including colostomy and plastic reconstruction of resulting defects upon resection.

Estimation of half-life periods in nonlinear data with fractional polynomials

Regression models are frequently used to model the functional relationship between an interesting outcome parameter and one or more potentially relevant explanatory variables. Objectives can be to set up as a prognostic model, for example, or an estimation model for a certain parameter of interest. Determining half-life periods can be viewed as a particular application of such an estimation model. However, specific to these modelling problems is that time-dependent active agent concentrations can be nonlinear. Concurrently, a major limitation to common regression approaches is the assumed linear relation of the investigated variables. Therefore, a more flexible approach is required to handle the problem of finding a model which fits the data adequately. One possibility is the use of fractional polynomials. The application of this modelling approach in a univariate setting is proposed in order to have an appropriate data model which subsequently serves as an estimation model for half-life periods. This estimation model includes Ridders’ method which is based on a regula falsi approach, a standard methodology of numerical analysis. The suggested procedure is applied to real data examples of antibiotic tissue concentrations in visceral surgery, nephropharmacology and clinical pharmacology and is furthermore compared to simple approaches of modelling nonlinear data.

Chondroid hamartoma of the liver.

A 60-year-old patient presented with a solitary mass within the right hepatic lobe. Diagnostic imaging revealed a solid tumor on the diameter of 3 cm. In absence of any extrahepatic manifestation and based on FNAC findings the lesion was classisfied a primary hepatic chondroid sarcoma. However, after right hemihepatectomy histologic assessment resulted the final diagnosis of a benign chondroid hamartoma. Our findings add another variant to the versatile phenotype of liver hamartoma.

Massive gastric dilatation caused by eating binges demanding surgical intervention: a case report

The clinical picture of an acute abdomen is frequently encountered in emergency medicine. In most cases abdominal pathologies underlie this condition, however, also extra-abdominal diseases may present or cause an acute abdomen. The fact that this condition is potentially life-threatening highlights the importance of instant action. Here, we report on the case of a young woman that presented with an acute abdomen in our clinic. Imaging revealed a massively distended stomach reaching the lesser pelvis. Initially, the etiology for the gastric dilatation remained unsolved. On the same day we performed an explorative laparotomy in which massive amounts of clotted, undigested food was recovered via a gastrotomy. Postoperatively, upon psychiatric consultation, an eating disorder with daily eating binges could be revealed as being the cause for the acute and dramatic gastric dilatation. The patient fully recovered from surgery and psychiatric co-treatment was initiated. This unique case report demonstrates how a psychiatric condition may lead to an acute abdomen, however, it also emphasizes the importance of prompt diagnosis and adequate therapy to avoid complications and allowing for full recovery.