Current clinical use of intravenous fosfomycin in ICU patients in two European countries.

PURPOSE: In Europe, intravenous fosfomycin (IV) is used particularly in difficult-to-treat or complex infections, caused by both Gram-positive and Gram-negative pathogens including multidrug-resistant strains. Here, we investigated the efficacy and safety of intravenous fosfomycin under real-life conditions. METHODS: Prospective, multi-center, and non-interventional study in patients with bacterial infections from 20 intensive care units (ICU) in Germany and Austria (NCT01173575). RESULTS: Overall, 209 patients were included (77 females, 132 males, mean age: 59 ± 16 years), 194 of which were treated in intensive care (APACHE II score at the beginning of fosfomycin therapy: 23 ± 8). Main indications (± bacteremia or sepsis) were infections of the CNS (21.5%), community- (CAP) and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP, 15.3%), bone and joint infections (BJI, 11%), abdominal infections (11%), and bacteremia (10.5%). Most frequently identified pathogens were S. aureus (22.3%), S. epidermidis (14.2%), Enterococcus spp. (10.8%), E. coli (12.3%) and Klebsiella spp. (7.7%). At least one multidrug-resistant (MDR) pathogen was isolated from 51 patients (24.4%). Fosfomycin was administered with an average daily dose of 13.7 ± 3.5 g over 12.4 ± 8.6 days, almost exclusively (99%) in combination with other antibiotics. The overall clinical success was favorable in 81.3% (148/182) of cases, and in 84.8% (39/46) of patients with ≥ 1 MDR pathogen. Noteworthy, 16.3% (34/209) of patients developed at least one, in the majority of cases non-serious, adverse drug reaction during fosfomycin therapy. CONCLUSION: Our data suggest that IV fosfomycin is an effective and safe combination partner for the treatment of a broad spectrum of severe bacterial infections in critically ill patients.

[Epidemiology, Diagnosis and Treatment of Adult Patients with Nosocomial Pneumonia - Update 2017 - S3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy, the German Radiological Society and the Society for Virology]. / Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie ­ Update 2017.

Nosocomial pneumonia (HAP) is a frequent complication of hospital care. Most data are available on ventilator-associated pneumonia. However, infections on general wards are increasing. A central issue are infections with multidrug resistant (MDR) pathogens which are difficult to treat in the empirical setting potentially leading to inappropriate use of antimicrobial therapy.This guideline update was compiled by an interdisciplinary group on the basis of a systematic literature review. Recommendations are made according to GRADE giving guidance for the diagnosis and treatment of HAP on the basis of quality of evidence and benefit/risk ratio.This guideline has two parts. First an update on epidemiology, spectrum of pathogens and antimicrobials is provided. In the second part recommendations for the management of diagnosis and treatment are given. New recommendations with respect to imaging, diagnosis of nosocomial viral pneumonia and prolonged infusion of antibacterial drugs have been added. The statements to risk factors for infections with MDR pathogens and recommendations for monotherapy vs combination therapy have been actualised. The importance of structured deescalation concepts and limitation of treatment duration is emphasized.

Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012". DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy wasdeveloped at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroupsand among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.(AU)

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012

Objective: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. Design: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. Methods: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Results: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7­9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO 2/FiO 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO 2/FI O 2<150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5­10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). Conclusions: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

[Epidemiology, diagnosis and treatment of adult patients with nosocomial pneumonia. S-3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy]. / Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie. S-3 Leitlinie der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin e.V., der Deutschen Gesellschaft für Infektiologie e.V., der Deutschen Gesellschaft für Hygiene und Mikrobiologie e.V., der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e.V. und der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V.

Nosocomial pneumonia (HAP) is a frequent complication of hospital care. Most data are available on ventilator-associated pneumonia. However infections on general wards are also increasing. A central issue are infections with multi drug resistant (MDR) pathogens which are difficult to treat particularly in the empirical setting potentially leading to inappropriate use of antimicrobial therapy. This guideline was compiled by an interdisciplinary group on the basis of a systematic literature review. Recommendations are made according to GRADE giving guidance for the diagnosis and therapy of HAP on the basis of quality of evidence and benefit/risk ratio. The guideline has two parts. First an update on epidemiology, spectrum of pathogens and antiinfectives is provided. In the second part recommendations for the management of diagnosis and treatment are given. Proper microbiologic work up is emphasized for knowledge of the local patterns of microbiology and drug susceptibility. Moreover this is the optimal basis for deescalation in the individual patient. The intensity of antimicrobial therapy is guided by the risk of infections with MDR. Structured deescalation concepts and strict limitation of treatment duration should lead to reduced selection pressure.

[Dabigatran therapy--perioperative management and interpretation of coagulation tests]. / Therapie mit Dabigatran. Periinterventionelles Management und Interpretation von Gerinnungstests.

UNLABELLED: Dabigatran, an oral, reversible direct factor IIa inhibitor, is approved in Europe for stroke prevention in atrial fibrillation and for the prevention of venous thromboembolism after elective hip and knee replacement. In contrast to vitamin K antagonists, a routine coagulation monitoring during the treatment with dabigatran etexilate is not necessary. However, in specific clinical situations such as invasive emergency procedures or serious haemorrhage, the actual anticoagulant status of dabigatran may be of importance for the treating clinician and can be assessed by clotting tests (aPTT, TT, ECT). The diluted thrombin time test (Hemoclot®), which is specifically calibrated for dabigatran, is useful for quantitative determination of the dabigatran serum concentration. In general, discontinuation of dabigatran etexilate 24 hours before standard elective surgery is sufficient to normalise the bleeding risk in patients with normal renal function. In patients with renal impairment and/or in the case of a high bleeding risk procedure the recommended duration of discontinuation is prolonged. If a bleeding episode occurs in a patient on dabigatran, further treatment should be based on the severity and localisation of the bleeding. A distinct feature of dabigatran is the possibility of effectively removing dabigatran from the circulation by haemodialysis. RECOMMENDATION: In the case of clinically minor bleedings, a delay in the administration of the next dabigatran etexilate dose is recommended. The length of the delay is based on the patient's individual thromboembolic risk. In minor bleedings the use of prothrombin complex concentrates is not indicated. In the case of moderate or major bleedings the main focus should be on stabilising the circulation by using fluids and blood products and, if a lesion can be identified, the local treatment thereof. If time and infrastructure is available, dialysis offers an effective and fast option to remove dabigatran out of the circulation. In the incidence of severe and life threatening bleedings, an additional, more complex haemostasis management is required. Besides haemodynamic stabilisation of the circulation, administration of prothrombin complex concentrates should not be delayed. It has to be kept in mind that standard laboratory coagulation parameters may not accurately reflect the effect of prothrombin complex concentrates in patients on dabigatran. Hence the effect of the prothrombin complex concentrate should be monitored clinically and adjusted by means of onset of coagulation in vivo.

Certoparin versus UFH to prevent venous thromboembolic events in the very elderly patient: an analysis of the CERTIFY study.

INTRODUCTION: There is an exponential rise of thromboembolic risk with age because of co-morbidities, immobility and pharmacotherapy. We aimed to investigate the benefits and risks of heparin prophylaxis in very elderly patients ≥80 years and the type of heparin used in a subgroup analysis of the CERTIFY trial. PATIENTS/METHODS: 3,239 patients were randomized to 3,000 U aXa o.d. certoparin or 5,000 IU t.i.d. unfractionated heparin (UFH) for 8-20 days. RESULTS: Patients ≥80 years (n=1,365) were more likely to be female, had a lower mean bodyweight, were more frequently using antiplatelets and had a GFR below 30 ml/min/1.73 m(2) more often than patients <80 years (n=1,875). The combined endpoint of proximal DVT, symptomatic non-fatal PE and VTE related death was experience by 5.26% of patients ≥80 years versus 3.51% in younger patients (OR 1.53; 95%CI 1.05-2.21; p=0.03). There were no significant differences in both minor (OR 1.11; 95%CI 0.75-1.62) and major (OR 2.53; 95%CI 0.93-6.86) bleeding risks. Certoparin and UFH were equally effective in reducing thromboembolic risk in either age group. The risk of any (OR 0.45; 95%CI 0.26-0.79) and minor bleeding (OR 0.42; 95%CI 0.23-0.78) was reduced with certoparin in the very elderly only. There were more adverse events in elderly patients (OR 1.26; 95%CI 1.1-1.46), but rates were otherwise comparable. CONCLUSIONS: The analysis confirmed the increased thromboembolic risk in very elderly patients, but demonstrated no increased bleeding risk. Certoparin and UFH were equally effective and safe with a reduced risk of minor bleeding complications with certoparin in the very elderly.

CERTIFY: prophylaxis of venous thromboembolism in patients with severe renal insufficiency.

Patients with severe renal insufficiency (sRI) have been suggested to be at an increased risk of bleeding with low-molecular-weight heparins (LMWH). We aimed at assessing the benefits and risks of certoparin in comparison to unfractionated heparin (UFH) in these patients. In this subgroup analysis of the CERTIFY trial, acutely ill, non-surgical patients ≥70 years received certoparin 3,000U aXa o.d. or UFH 5,000 IU t.i.d. One hundred eighty-nine patients had a glomerular filtration rate (GFR) ≤30 ml/min/1.73 m2, 3,050 patients served as controls. Patients with sRI had a mean age of 85.9 ± 6.6 years (controls 78.4 ± 6.0) and were treated for a mean of 9.3 ± 3.7 days (9.9 ± 4.3). Thromboembolic event rates were comparable (4.55 vs. 4.21%; OR1.08; 95%CI 0.5-2.37) but bleeding was increased in sRI (9.52 vs. 3.54%; OR2.87; 95%CI 1.70-4.83). The incidence of the combined end-point of proximal DVT, symptomatic non-fatal PE and VTE related death was 6.49% with certoparin and 2.60% with UFH (OR2.60; 95%CI 0.49-13.85). There was a decrease in total bleeding with certoparin (OR0.33; 95%CI 0.11-0.97), which was non-significant in patients with GFR >30 ml/min/1.73 m2. In two multivariable regression models certoparin and immobilisation <10 days were associated with less bleeding while a GFR ≤30 ml/min/1.73 m2 was associated with increased bleeding. A total of 11.3% of certoparin- and 18.5% of UFH-treated patients experienced serious adverse events (14.8 in patients with a GFR ≤30 vs. 5.6% vs. >30 ml/min/1.73 m2). In conclusion, certoparin 3,000U anti Xa o.d. was as efficacious as 5,000 IU UFH t.i.d. in patients with sRI but had a reduced risk of bleeding.

Monozygotic twins discordant for trisomy 18.

We report on the pre- and postnatal cytogenetic, molecular genetic and clinical findings in monochorionic-diamniotic twins discordant for trisomy 18. Structural anomalies were identified in one of the twins on prenatal ultrasound examination at 20 weeks' gestation and sampling of amniotic fluid from both sacs was performed for karyotyping. This revealed trisomy 18 in the twin with abnormalities and a normal karyotype in the other twin. Elective Cesarean section was performed at 31 + 5 weeks and the aneuploid twin died shortly after delivery. The surviving twin showed low-grade mosaicism for trisomy 18 on postnatal analysis but has shown normal development. For prenatal diagnosis in monochorionic-diamniotic twin pregnancy the sampling of both amniotic sacs is recommended, especially if one twin has structural anomalies on ultrasound scan.