An Open, Randomized, Single-Center, Crossover Pharmacokinetic Study of Meropenem after Intraperitoneal and Intravenous Administration in Patients Receiving Automated Peritoneal Dialysis.

The objective of this study was to determine the pharmacokinetic profile of meropenem in automated peritoneal dialysis (APD) patients. In 6 patients without peritonitis, a single dose of 0.5 g of meropenem was applied intraperitoneally (i.p.) or intravenously (i.v.) and concentrations in serum and dialysate were measured at specified intervals over 24 h with high-performance liquid chromatography-mass spectrometry. The mean maximum concentrations of meropenem in serum (Cmax) were 27.2 mg/liter (standard deviation [SD], ±6.9) and 10.1 mg/liter (SD, ±2.5) and in dialysate were 3.6 mg/liter (SD, ±2.3) and 185.8 mg/liter (SD, ±18.7) after i.v. and i.p. administrations, respectively. The mean areas under the curve from 0 to 24 (AUC0-24) of meropenem in serum were 173.5 mg · h/liter (SD, ±29.7) and 141.4 mg · h/liter (SD, ±37.5) (P = 0.046) and in dialysate were 42.6 mg · h/liter (SD, ±20.0) and 623.4 mg · h/liter (SD, ±84.1) (P = 0.028) after i.v. and i.p. administrations, respectively. The ratios for dialysate exposure over plasma exposure after i.v. and i.p. treatments were 0.2 (SD, ±0.1) and 4.6 (SD, ±0.9), respectively (P = 0.031). A mean target value of 40% T>MIC (time for which the free meropenem concentration exceeds the MIC) for clinically relevant pathogens with EUCAST susceptibility breakpoints of 2 mg/liter was reached in serum after i.p. and i.v. administrations and in dialysate after i.p. but not after i.v. administration. The present data indicate that low i.p. exposure limits the i.v. use of meropenem for PD-associated peritonitis. In contrast, i.p. administration not only results in superior concentrations in dialysate but also might be used to treat systemic infections.

Cardiovascular Morbidity and Pure Red Cell Aplasia Associated With Epoetin Theta Therapy in Patients With Chronic Kidney Disease: A Prospective, Noninterventional, Multicenter Cohort Study.

PURPOSE: The European Medicines Agency recommends limiting the hemoglobin (Hb) concentration to 10 to 12 g/dL in adults with chronic kidney disease (CKD) receiving erythropoiesis-stimulating agents such as epoetin theta. This postauthorization study assessed the incidence and intensity of cardiovascular events, including ischemic stroke, in patients receiving epoetin theta for anemia associated with CKD. A secondary end point was adverse drug reactions, including pure red cell aplasia. METHODS: In this prospective, noninterventional, multinational cohort study, consecutive patients with advanced or end-stage renal disease and receiving epoetin theta were followed up for 6 months. Data on reportable adverse events (RAEs) (cardiac disorders, cardiac failure, myocardial infarction, and ischemic stroke and respective subterms), epoetin theta dosage, and Hb concentrations were collected. A post hoc exploratory analysis assessed the incidences of RAEs according to tertiles for individual mean Hb concentration (≤10.7, >10.7-11.47, and >11.47 g/dL for low, intermediate, and high, respectively) and mean weekly epoetin theta dosage (≤62, >62-125, and >125 IU/kg/wk for low, intermediate, and high). FINDINGS: Data from 1039 patients were included (577 men, 462 women; mean age, 68.7 years). A total of 101 RAEs were documented in 89 patients (8.6%), for an event rate of 0.1985/person-year. Sixty-four patients (6.1%) died; none of the deaths was considered related to epoetin theta use. The incidence of RAEs was lowest at intermediate Hb concentrations (6.2%) compared with low (11.3%) and high (7.8%) Hb concentrations. The incidence of ischemic stroke was 1.5% at high Hb concentrations versus 0.6% at both the low and intermediate Hb concentrations. The incidence of any RAE was greater in the high-dose group (10.1%) than in the intermediate-dose (8.0%) and low-dose (7.6%) groups. The risk for any cardiovascular RAE or ischemic stroke was greatest in the high-dose/high-Hb group (13.3%), followed by high dose/low Hb (12.6%) and low dose/low Hb (12.1%). The risks for RAEs were lowest at high dose/intermediate Hb (3.8%) and low dose/intermediate Hb (5.3%). The event rate of adverse drug reactions other than the predefined RAEs was 0.0161/person-year. No cases of pure red cell aplasia were reported. IMPLICATIONS: The findings from the present study suggest that, for maintaining the optimal target Hb concentration (10-12 g/dL according to the current summary of product characteristics for epoetin theta; 10-11.5 g/dL according to the current guideline from Kidney Disease Improving Global Outcomes) in anemic adults with CKD, the lowest approved, effective dose epoetin theta should be used.

Anemia prevalence and treatment practice in patients with non-myeloid tumors receiving chemotherapy.

PURPOSE: To describe the prevalence and management of anemia in cancer patients. METHODS: This cross-sectional, observational survey was conducted in Italy and Austria. Centers prespecified one day, during a 4-month enrollment window, to report specific data collected during normal clinical practice for patients with non-myeloid tumors attending for chemotherapy (±radiotherapy) treatment. The primary endpoint was the prevalence of anemia as determined using a prespecified algorithm: hemoglobin (Hb) ≤10 g/dL on/within 3 days prior to visit; ongoing anemia treatment; physician diagnosis of anemia, together with ≥1 anemia symptom. RESULTS: Between November 18, 2010 and March 18, 2011, data for 1412 patients were collected (Italy n = 1130; Austria n = 282). Most patients (n = 1136; 80%) had solid tumors; 809 (57%) had received ≤3 chemotherapy cycles. The prevalence of anemia was 32% (95% confidence interval: 29.4%-34.2%); 196 patients (14%) were deemed anemic based on Hb ≤10 g/dL, 131 (9%) on ongoing anemia treatment, and 121 (9%) on physician diagnosis/anemia symptom. Overall, 1153 patients (82%) had Hb data; mean (standard deviation [SD]) Hb levels were 11.7 (1.7) g/dL. In total, 456 patients (32%) had anemia symptoms: fatigue (n = 392; 28%), depression (n = 122; 9%), and dyspnea (n = 107; 8%) were most common. Fifty-one patients (4%) had had their current chemotherapy cycle delayed due to anemia. On visit day, or ≤28 days prior, 91 (6%), 188 (13%), and 81 patients (6%) had evidence of whole blood/red blood cell transfusion, erythropoiesis-stimulating agent use, or iron use, respectively. CONCLUSION: On the prespecified study day, one-third of patients with non-myeloid tumors undergoing chemotherapy were found to be anemic and 13% had evidence of erythropoiesis-stimulating agent use then or in the 28 days prior.

Treatment with oral active vitamin D is associated with decreased risk of peritonitis and improved survival in patients on peritoneal dialysis.

Peritonitis is a major complication of peritoneal dialysis (PD) being associated with hospitalization, catheter loss, technique failure, and increased mortality. Data on incidence rates and risk factors for peritonitis episodes vary between centers. In seven Austrian PD units clinical and laboratory data on each peritonitis episode were collected from all patients (n = 726) who performed PD between January 2000 and December 2009. The peritonitis incidence rate was 0.32 episodes/patient-year. In a multivariate analysis the risk of peritonitis was decreased by 57% in patients treated with oral active vitamin D (HR 0.43; 95% CI 0.28-0.64). Renal disease classified as "other or unknown" (HR 1.65; 95% CI 1.08-2.53) and serum albumin <3500 mg/dl (HR 1.49; 95% CI 1.04-2.15) were also associated with an increased risk of peritonitis. Albumin levels <3500 mg/dl (HR 1.89; 95% CI 1.13-3.17), age (HR 1.06 per year; 95% CI 1.03-1.09), and cardiomyopathy (HR 3.01; 95% CI 1.62-5.59) were associated with increased mortality, whereas treatment with oral active vitamin D was associated with a significantly lower risk of death (HR 0.46; 95% CI 0.27-0.81). In this retrospective multi-center study we identified several factors being related to increased risk of peritonitis in PD patients. Treatment with oral active vitamin D was identified as being independently associated with decreased risk of peritonitis, and decreased all-cause mortality in PD patients.

Case Report: Pregnancy in a patient with recurrent glioblastoma.

We report the case of a woman with relapsed glioblastoma multiforme (GBM) who recently gave birth. She announced her pregnancy shortly after the sixth cycle of a dense regimen of temozolomide, prescribed for treating the first recurrence of glioblastoma. Three years ago, in April 2008, she had undergone gross total resection of a glioblastoma multiforme in the postcentral region of the right hemisphere and had subsequently received treatment according to the actual standard therapy consisting of radiotherapy up to 60 Gy with concomitant and adjuvant temozolomide. The complete amount of temozolomide given before this pregnancy was 20.9 mg/m (2). Nevertheless, she delivered a 1890 g child by caesarean section in the 32/6 week of pregnancy. The child showed no anomalies and is developing normally under close surveillance by paediatricians.

Outbreak of leptospirosis among triathlon participants in Langau, Austria, 2010.

We report on the first documented outbreak of leptospirosis in Austria. In July 2010, four cases of serologically confirmed leptospirosis occurred in athletes after a triathlon held in Langau. Heavy rains preceded the triathlon (rainfall: 22 mm). The index case (Patient A) was a 41-year-old previously healthy male, who was admitted to hospital A on July 8 with a four-day history of fever up to 40°C that began 14 days after attending the triathlon event. On July 7, patient B, a 42-year-old male, was admitted to the same hospital, with signs and symptoms of kidney failure. Hemodialysis was performed every other day for 3 weeks. While the serum drawn on the day of admission was negative for antibodies against Leptospira, a specimen from July 28 tested positive with Leptospira interrogans. On July 11, patient C, a 40-year-old male, was admitted to hospital B for nephritis. On July 14, patient D, a 44-year-old male, was admitted to hospital C with a ten days history of intermittent fever, mild dry cough and headache. Our report underlines that in Austria recreational users of bodies of freshwater must be aware of an existing risk of contracting leptospirosis, particularly after heavy rains. The suppressive influence of a triathlon on the immune system is well documented and therefore an outbreak in this population group can be seen as a sensitive indicator concerning possible risk for the general population.

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer.

BACKGROUND: Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. METHODS: A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. RESULTS: Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. CONCLUSION: There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.

Initial body mass indexes have contrary effects on change in body weight and mortality of patients on maintenance hemodialysis treatment.

Malnutrition is a relevant risk factor for mortality for patients on maintenance hemodialysis treatment. In a retrospective study including 377 patients who began hemodialysis treatment between 1986 and 2001, we assessed the prevalence of different statuses of nutrition and the impact of the initial status of nutrition on the change in body weight and patient survival. We found an inverse relationship between body mass index (BMI, kg/m2) and the gain in body weight and BMI within 12 months of hemodialysis treatment. Underweight and normal weight patients had a substantial increase in these parameters, greatest in underweight subjects, whereas overweight and obese patients showed only a moderate increase or none (P =.0019, P =.00036). Adjusted mortality rates showed an inverse correlation with the initial BMI (P <.0001). There was a statistically significant difference in the mortality between patients with normal weight and overweight or obesity, respectively, showing a more favorable prognosis in overweight and obese patients (P =.0007; P =.022; log-rank, normal versus overweight, P =.012). Weight loss was the greatest independent risk factor for mortality in general. Adjusted hazard ratio of death was highest in underweight patients (3.999; CI, 2.708 to 5.905; P <.0001) and decreased to 2.251 (CI, 1.795 to 2.822; P <.0001) in normal weight, 1.927 (CI, 1.390 to 2.670; P <.0001) in overweight, and 1.651 (CI, 0.841 to 3.236; P =.1439) in obese subjects when patients with weight loss were compared with patients who preserved their initial weight or gained weight. Overall, the initial BMI has an influence on the change in body weight as well as on patient survival in general and in the case of weight loss in particular.