Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation.

Infections are a leading cause of death in stroke patients. In a mouse model of focal cerebral ischemia, we tested the hypothesis that a stroke-induced immunodeficiency increases the susceptibility to bacterial infections. 3 d after ischemia, all animals developed spontaneous septicemia and pneumonia. Stroke induced an extensive apoptotic loss of lymphocytes and a shift from T helper cell (Th)1 to Th2 cytokine production. Adoptive transfer of T and natural killer cells from wild-type mice, but not from interferon (IFN)-gamma-deficient mice, or administration of IFN-gamma at day 1 after stroke greatly decreased the bacterial burden. Importantly, the defective IFN-gamma response and the occurrence of bacterial infections were prevented by blocking the sympathetic nervous system but not the hypothalamo-pituitary-adrenal axis. Furthermore, administration of the beta-adrenoreceptor blocker propranolol drastically reduced mortality after stroke. These data suggest that a catecholamine-mediated defect in early lymphocyte activation is the key factor in the impaired antibacterial immune response after stroke.

Impact of adherence to standard operating procedures for pneumonia on outcome of intensive care unit patients.

BACKGROUND: Pneumonia accounts for almost half of intensive care unit (ICU) infections and nearly 60% of deaths from nosocomial infections. It increases hospital stay by 7-9 days, crude mortality by 70% and attributable mortality by 30%. OBJECTIVE: Our purpose was to assess the impact of standard operating procedures adapted to the local resistance rates in the initial empirical treatment for pneumonia on duration of first pneumonia episode, duration of mechanical ventilation, and length of ICU stay. DESIGN: Prospective observational cohort study with retrospective expert audit. SETTING: Five anesthesiologically managed ICUs at University hospital (one cardio-surgical, one neurosurgical, two interdisciplinary, and one intermediate care). PATIENTS: Of 524 consecutive patients with > or = 36 hr ICU treatment 131 patients with pneumonia on ICU were identified. Their first pneumonia episode was evaluated daily for adherence to standard operating procedures. Pneumonia was diagnosed according to the American Thoracic Society guidelines. Patients with > 70% compliance were assigned to high adherence group (HAG), patients with < or = 70% to low adherence group (LAG). MEASUREMENTS AND RESULTS: HAG consisted of 45 (49 first episode) patients, LAG of 86 (82 first episode) patients, respectively. Mean duration of treatment of the first pneumonia episode was 10.11 +/- 7.95 days in the LAG and 6.22 +/- 3.27 days in the HAG (p = 0.001). Duration of mechanical ventilation was 317.59 +/- 336.18 hrs in the LAG and 178.07 +/- 191.33 hrs in the HAG (p = 0.017). Length of ICU stay was 20.24 +/- 16.59 days in the LAG and 12.04 +/- 10.42 days in the HAG (p = 0.001). LIMITATIONS: Barriers in compliance need further evaluation. CONCLUSION: Adherence to standard operating procedure is associated with a shorter duration of treatment of first pneumonia episode, a shorter duration of mechanical ventilation, and a shorter ICU stay.

[Evidence-based anti-infective program "ABx" - Online-program for anti-infective therapy broadens functions for local adaptations]. / Evidenzbasiertes Antiinfektiva-Programm "ABx" - Neue Möglichkeiten durch lokale Anpassung.

National and international evidence based recommendations for anti-infective therapies in the intensive care unit are difficult to implement into daily clinical work. However, adequate and early applications of anti-infective therapies are important outcome factors for the clinical course of severe infections. With support of the German Society of Anaesthesiology and Intensive Care Medicine and the Association of German Anaesthesiologists (DGAI/BDA) a web based anti-infective program was developed to address these issues. The program includes interdisciplinary consented evidence based algorithms to help with immediate diagnostics and initial anti-infective therapies. Currently, with the title "ABx local" a subproject is launched to broaden program functions. It unifies current evidence based recommendations and local internal standards or comments on one platform to achieve priority of therapy options e.g. based on resistance patterns.

Fluorescence in situ hybridisation (FISH) accelerates identification of Gram-positive cocci in positive blood cultures.

Sepsis is a life-threatening disease with a high mortality rate. Rapid identification of blood culture isolates plays a crucial role in adequate antimicrobial therapy in sepsis patients. To accelerate microbiological diagnosis, a comprehensive panel of oligonucleotide probes for fluorescence in situ hybridisation (FISH) targeting Gram-positive cocci was compiled and evaluated on 428 positive blood culture specimens. By combining genus-specific and species-specific probes, the assay allowed discrimination of staphylococci, streptococci and enterococci as well as differentiation of therapy-relevant pathogens such as Staphylococcus aureus and Enterococcus faecium/durans. Furthermore, the newly designed FISH probes STREP2, ENCO and GRANU targeted Streptococcus pneumoniae/mitis, Enterococcus spp. (except E. faecalis) and Granulicatella adiacens group, respectively. The FISH assay achieved an overall sensitivity of 98.65% and a specificity of 99.0% and therefore allowed rapid and reliable molecular identification of Gram-positive cocci in blood culture specimens.

Early outcome after surgery for active native and prosthetic aortic valve endocarditis.

BACKGROUND AND AIM OF THE STUDY: Today, the in-hospital mortality of patients treated surgically for active aortic native and prosthetic valve endocarditis remains high. The study aim was to identify the preoperative and intraoperative predictors of early outcome. METHODS: Between January 2004 and December 2006, 75 patients (57 males, 18 females; mean age 61.6 +/- 14.1 years) underwent surgery for active native valve (NVE) or prosthetic aortic valve endocarditis (PVE). RESULTS: Active aortic NVE was present in 49 patients (65.3%), and PVE in 26 (34.7%). Staphylococcus species were the most common infecting microorganisms in both groups, while 20 cases (26.7%) were culture-negative. Except for significantly higher preoperative renal failure (RF) in patients with PVE (p = 0.01), the clinical characteristics were equally distributed. Four patient subsets were identified based on the extent of the infectious process: (i) locally controlled NVE (38.7%); (ii) locally uncontrolled NVE (26.7%); (iii) locally controlled PVE (14.6%); and (iv) locally uncontrolled PVE (20%). Aortic valve replacement (AVR) was performed with a stentless bioprosthesis in 53 cases (70.7%), a mechanical prosthesis in eight (10.6%), and a Ross procedure in 14 (18.7%). Concomitant active mitral valve endocarditis was treated in 17 patients (22.7%). Associated procedures were performed in 14 cases (18.7%). The in-hospital mortality was 24% (n = 18). Female gender (p = 0.0147), preoperative septic or cardiogenic shock (p = 0.0275) and previous embolic events (p = 0.0129) were identified as independent predictors for in-hospital mortality. Eight late deaths occurred; the estimated overall actuarial survival was 66.6 +/- 5.6% at 12 months and 60.7 +/- 6.5% at 24 months. On Cox multiple regression, age > 70 years (p = 0.0113), preoperative RF (p = 0.0015) and mitral valve surgery due to concomitant infective endocarditis (p = 0.0363) were significant adverse predictors of late death. CONCLUSION: Surgery for active aortic valve infective endocarditis is associated with high operative mortality and morbidity. Failure of antibiotic therapy causing septic or cardiogenic shock and delayed referral to surgery may have a detrimental effect on early outcome. Surgical eradication of cardiac infections should always be associated with the treatment of extracardiac septic foci, which could maintain a septic state and adversely influence early outcome. Adhesion to surgical guidelines, together with a multidisciplinary approach, may have a major impact on the early prognosis of these high-risk patients.

[Strategies in the treatment of infections with antibiotics in intensive care medicine]. / Strategien für die Verordnung von Antibiotika in der Intensivmedizin.

The treatment of infections is one of the central elements in post-operative intensive care and contributes significantly to outcome. Measures of quality of antibiotic therapy include survival, duration of ICU or in-patient stay and rates of organ failure, antibiotic resistance or nosocomial infection. The pre-requisites for antibiotic prescribing in the intensive care unit are as follows: the treatment has to be started early, the antibiotic must be effective against probable causative organisms, the patient's risk factors for infection with multi-drug resistant organisms must be taken into account, local patterns of resistance must be known, an effective dosage must be used and the duration of therapy should be adjusted to the patient's risk factors and probable causative organisms. The multiplicity of factors which must be taken into account when determining timely empirical therapy and the fact that this must be possible at any time of the day, make local standard operating procedures for antibiotic prescribing imperative. These standards should reflect local resistance patterns and should be regularly reviewed. The aim of this educational article is to portray a selection of the pre-requisites and strategies available in the treatment of infections with antibiotics in intensive care medicine.

[Implementation of standard operating procedures for the initial empirical antimicrobial therapy for adults--a new computer program at the University Hospital Charité]. / Einführung von SOPs zur initialen kalkulierten Antibiotikatherapie bei Erwachsenen--Ein neues Computerprogramm an der Charité.

Nowadays 40-50 % of the patients receive inappropriate antibiotic treatment. Evidence based recommendations are not considered and there is an increasing burden of resistant pathogens. Therefore, standard operating procedures (SOPs) should be implemented considering guidelines and resistant species in the specific ICU. The authors developed algorithms and generated a user friendly computer program available for all ICU physicians all the time.

Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke.

BACKGROUND AND PURPOSE: Epidemiological studies have demonstrated a high incidence of infections after severe stroke and their prominent role in morbidity and mortality in stroke patients. In a mouse model, it has been shown recently that stroke is coupled with severe and long-lasting immunosuppression, which is responsible for the development of spontaneous systemic infections. Here, we investigated in the same model the effects of preventive antibiotic treatment on survival and functional outcome of experimental stroke. METHODS: Mice were subjected to experimental stroke by occlusion of the middle cerebral artery (MCAO) for 60 minutes. A group of mice received moxifloxacin (6x100 mg/kg body weight every 2 hours over 12 hours) either immediately or 12 hours after MCAO. Control animals received the vector only. Behavior, neurological deficit, fever, survival, and body weight were monitored over 14 days. In a subgroup, infarct volume was measured 4 days after MCAO. Microbiological assessment was based on cultures of lung tissue, blood, and feces of animals 3 days after stroke. For a dose-response study, moxifloxacin was given immediately after MCAO in different doses and at different time points. RESULTS: Microbiological analyses of blood and lung tissue demonstrated high bacterial burden, mainly Escherichia coli, 3 days after stroke. Accordingly, we observed clinical and histological signs of septicemia and pneumonia. Moxifloxacin prevented the development of infections and fever, significantly reduced mortality, and improved neurological outcome. CONCLUSIONS: Preventive antibiotic treatment may be an important new therapeutical approach to improve outcome in patients with severe stroke.

Timing the valve replacement in infective endocarditis involving the brain.

Neurological complications are very frequent in patients with infective endocarditis (20-40 %). In these patients it is unclear at what time a valve replacement should be performed. In order to develop a data based recommendation we studied 12 patients of our own and analyzed 228 patients from the literature. We included patients with valve replacement after a neurological complication of endocarditis and documented the time between manifestation and operation and the outcome. Based on these 240 patients we calculated the risk of neurological deterioration after the valve replacement. After brain infarction this risk is 20% within three days, 20-50% between day 4 and 14, but declines to < 10% after 14 days and < 1% after 4 weeks. Valve replacement within the first four weeks after intracranial hemorrhage has been reported to be successful only in individual cases. The risk of deteriorating declines later to 15%. Based on these limited data we suggest that valve replacement in patients with brain infarction should be considered within the first 72 hours if they have severe heart failure, otherwise after four weeks. Only a few selected patients with intracranial hemorrhage and progressive heart failure might benefit from valve replacement within the first four weeks. For all other neurological complications there are no reliable data. We propose a structured approach depending on cardiac and neurological complications and the time course of the disease.

Outbreak of carbapenem-resistant Acinetobacter baumannii carrying the carbapenemase OXA-23 in a German university medical centre.

A prolonged outbreak of carbapenem-resistant Acinetobacter baumannii in a German university medical centre in 2006 was investigated; the investigation included a descriptive epidemiological analysis, a case-control study, environmental sampling, molecular typing of A. baumannii isolates using PFGE and repetitive-sequence-based PCR (rep-PCR) typing, and detection of OXA-type carbapenemases by multiplex PCR. Thirty-two patients acquired the outbreak strain in five intensive care units (ICUs) and two regular wards at a tertiary care hospital within 10 months. The outbreak strain was resistant to penicillins, cephalosporins, ciprofloxacin, gentamicin, tobramycin, imipenem and meropenem, and carried the bla(OXA-23)-like gene. Based on PFGE and rep-PCR typing, it was shown to be related to the pan-European A. baumannii clone II. The most likely mode of transmission was cross-transmission from colonized or infected patients via the hands of health-care workers, with the severity of disease and intensity of care (therapeutic intervention scoring system 28 score >median) being independently associated with acquisition of the outbreak strain (odds ratio 6.67, 95 % confidence interval 1.55-36.56). Control of the outbreak was achieved by enforcement of standard precautions, education of personnel, screening of ICU patients for carbapenem-resistant A. baumannii and cohorting of patients. This is believed to be the first report of an outbreak of A. baumannii carrying the carbapenemase OXA-23 in Germany.

Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial.

BACKGROUND: Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients. METHODS: Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance. FINDINGS: On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections. INTERPRETATION: PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN74386719.

How many infections are caused by patient-to-patient transmission in intensive care units?

OBJECTIVE: The proportion of intensive care unit (ICU)-acquired infections that are a consequence of nosocomial cross-transmission between patients in tertiary ICUs is unknown. Such information would be useful for the implementation of appropriate infection control measures. DESIGN: A prospective cohort study during 18 months. SETTING: Five ICUs from two university hospitals. PATIENTS: All patients admitted for >/=48 hrs. MEASUREMENT: ICU-acquired infections were ascertained during daily bedside patient and chart reviews. Episodes of potential cross-transmission were identified by highly discriminating genetic typing of all clinical and surveillance isolates of the ten bacterial species most frequently associated with nosocomial infections in ICUs. Isolation of indistinguishable isolates in two or more patients defined potential transmission episodes. MAIN RESULTS: During 28,498 patient days, 431 ICU-acquired infections and 141 episodes of nosocomial transmissions were identified. A total of 278 infections were caused by the ten species that were genotyped, and 41 of these (14.5%) could be associated with transmissions between patients. CONCLUSION: Infections acquired during treatment in modern tertiary ICUs are common, but a causative role of direct patient-to-patient transmission can only be ascertained for a minority of these infections on the basis of routine microbiological investigations.

Naturally occurring anti-IFN-gamma autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans.

Recently various genetic defects in immunity mediated by interferon gamma (IFN-gamma) have been described, including mutations in the IFN-gamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2), signal transducer and activator of transcription 1 (STAT 1), and interleukin 12 receptor beta 1 (IL-12Rbeta1), and IL-12 p40 genes. These mutations are associated with the occurrence of severe infections with intracellular pathogens especially nontuberculous mycobacteria and vaccine-associated bacilli Calmette-Guérin (BCG). Here we report data on a previously healthy adult patient primarily presenting with severe infections with Burkholderia cocovenenans and subsequently Mycobacterium cheloneae. We found a strong inhibitory anti-IFN-gamma activity in the patient's plasma and identified a high-affinity neutralizing anti-IFN-gamma autoantibody. Unfortunately, the patient died due to severe sepsis before we knew the nature of the inhibitory activity. The application of alternative therapeutic approaches such as intravenous immunoglobulin or immunoadsorption may have been beneficial in this case. Screening for neutralizing anti-IFN-gamma autoantibodies should supplement testing for IFN-gamma and IL-12 pathway defects in patients with recurrent infections with intracellular pathogens, especially with nontuberculous mycobacteria.