Six-month outcomes after individualized nutritional support during the hospital stay in medical patients at nutritional risk: Secondary analysis of a prospective randomized trial.

BACKGROUND: Among medical inpatients at risk of malnutrition, the use of individualized nutritional support during the hospital stay was found to reduce complications and improve mortality at short-term. We evaluated clinical outcomes at 6-months follow-up. METHODS: We randomly assigned 2028 patients to receive protocol-guided individualized nutritional support to reach protein and energy goals (intervention group) or hospital food as usual (control group) during the hospital stay. The intervention was discontinued at hospital discharge and further nutritional support was based on the discretion of the treating team. We had complete follow-up information of 1995 patients (98%), which were included in the final analysis. The primary endpoint was all-cause mortality at 6-months. Prespecified secondary end points included non-elective hospital readmissions, functional outcome and quality of life. RESULTS: At 6-month, 231 of 994 (23.2%) intervention group patients had died compared to 246 of 999 (24.6%) control group patients, resulting in a hazard ratio for death of 0.90 (95%CI 0.76 to 1.08, p = 0.277). Compared to control patients, intervention group patients had similar rates of hospital readmission (27.3% vs. 27.6%, HR 1.00 (95%CI 0.84 to 1.18), p = 0.974), falls (11.2% vs. 10.9%, HR 0.96 (95%CI 0.72 to 1.27), p = 0.773) and similar quality of life and activities of daily living scores. INTERPRETATION: While individualized nutritional support during the hospital stay significantly reduced short-term mortality, there was no legacy effect on longer term outcomes. Future trials should investigate whether continuation of nutritional support after hospital discharge reduces the high malnutrition-associated mortality rates in this vulnerable patient population. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02517476.

Individualised nutritional support in medical inpatients at nutritional risk: a randomised clinical trial.

BACKGROUND: Guidelines recommend the use of nutritional support during hospital stays for medical patients (patients not critically ill and not undergoing surgical procedures) at risk of malnutrition. However, the supporting evidence for this recommendation is insufficient, and there is growing concern about the possible negative effects of nutritional therapy during acute illness on recovery and clinical outcomes. Our aim was thus to test the hypothesis that protocol-guided individualised nutritional support to reach protein and caloric goals reduces the risk of adverse clinical outcomes in medical inpatients at nutritional risk. METHODS: The Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) is a pragmatic, investigator-initiated, open-label, multicentre study. We recruited medical patients at nutritional risk (nutritional risk screening 2002 [NRS 2002] score ≥3 points) and with an expected length of hospital stay of more than 4 days from eight Swiss hospitals. These participants were randomly assigned (1:1) to receive either protocol-guided individualised nutritional support to reach protein and caloric goals (intervention group) or standard hospital food (control group). Randomisation was done with variable block sizes and stratification according to study site and severity of malnutrition using an interactive web-response system. In the intervention group, individualised nutritional support goals were defined by specialist dietitians and nutritional support was initiated no later than 48 h after admission. Patients in the control group received no dietary consultation. The composite primary endpoint was any adverse clinical outcome defined as all-cause mortality, admission to intensive care, non-elective hospital readmission, major complications, and decline in functional status at 30 days, and it was measured in all randomised patients who completed the trial. This trial is registered with ClinicalTrials.gov, number NCT02517476. FINDINGS: 5015 patients were screened, and 2088 were recruited and monitored between April 1, 2014, and Feb 28, 2018. 1050 patients were assigned to the intervention group and 1038 to the control group. 60 patients withdrew consent during the course of the trial (35 in the intervention group and 25 in the control group). During the hospital stay, caloric goals were reached in 800 (79%) and protein goals in 770 (76%) of 1015 patients in the intervention group. By 30 days, 232 (23%) patients in the intervention group experienced an adverse clinical outcome, compared with 272 (27%) of 1013 patients in the control group (adjusted odds ratio [OR] 0·79 [95% CI 0·64-0·97], p=0·023). By day 30, 73 [7%] patients had died in the intervention group compared with 100 [10%] patients in the control group (adjusted OR 0·65 [0·47-0·91], p=0·011). There was no difference in the proportion of patients who experienced side-effects from nutritional support between the intervention and the control group (162 [16%] vs 145 [14%], adjusted OR 1·16 [0·90-1·51], p=0·26). INTERPRETATION: In medical inpatients at nutritional risk, the use of individualised nutritional support during the hospital stay improved important clinical outcomes, including survival, compared with standard hospital food. These findings strongly support the concept of systematically screening medical inpatients on hospital admission regarding nutritional risk, independent of their medical condition, followed by a nutritional assessment and introduction of individualised nutritional support in patients at risk. FUNDING: The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau, Switzerland.

Extended Versus Limited Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Survival Results from a Prospective, Randomized Trial.

BACKGROUND: The extent of lymph node dissection (LND) in bladder cancer (BCa) patients at the time of radical cystectomy may affect oncologic outcome. OBJECTIVE: To evaluate whether extended versus limited LND prolongs recurrence-free survival (RFS). DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, phase-III trial patients with locally resectable T1G3 or muscle-invasive urothelial BCa (T2-T4aM0). INTERVENTION: Randomization to limited (obturator, and internal and external iliac nodes) versus extended LND (in addition, deep obturator, common iliac, presacral, paracaval, interaortocaval, and para-aortal nodes up to the inferior mesenteric artery). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was RFS. Secondary endpoints included cancer-specific survival (CSS), overall survival (OS), and complications. The trial was designed to show 15% advantage of 5-yr RFS by extended LND. RESULTS AND LIMITATIONS: In total, 401 patients were randomized from February 2006 to August 2010 (203 limited, 198 extended). The median number of dissected nodes was 19 in the limited and 31 in the extended arm. Extended LND failed to show superiority over limited LND with regard to RFS (5-yr RFS 65% vs 59%; hazard ratio [HR]=0.84 [95% confidence interval 0.58-1.22]; p=0.36), CSS (5-yr CSS 76% vs 65%; HR=0.70; p=0.10), and OS (5-yr OS 59% vs 50%; HR=0.78; p=0.12). Clavien grade ≥3 lymphoceles were more frequently reported in the extended LND group within 90d after surgery. Inclusion of T1G3 tumors may have contributed to the negative study result. CONCLUSIONS: Extended LND failed to show a significant advantage over limited LND in RFS, CSS, and OS. A larger trial is required to determine whether extended compared with limited LND leads to a small, but clinically relevant, survival difference (ClinicalTrials.gov NCT01215071). PATIENT SUMMARY: In this study, we investigated the outcome in bladder cancer patients undergoing cystectomy based on the anatomic extent of lymph node resection. We found that extended removal of lymph nodes did not reduce the rate of tumor recurrence in the expected range.

Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme.

BACKGROUND: Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue. METHODS: The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model. RESULTS: 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%-24% in the total cohort and by 24%-31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores. CONCLUSIONS: This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study.

Correction to: Catheter retention as a consequence rather than a cause of unfavorable outcome in candidemia.

In the original publication the members of the FUNGINOS network were provided in such a way that they could not be indexed as collaborators on PubMed.

Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study.

OBJECTIVES: Breakthrough candidemia (BTC) on fluconazole was associated with non-susceptible Candida spp. and increased mortality. This nationwide FUNGINOS study analyzed clinical and mycological BTC characteristics. METHODS: A 3-year prospective study was conducted in 567 consecutive candidemias. Species identification and antifungal susceptibility testing (CLSI) were performed in the FUNGINOS reference laboratory. Data were analyzed according to STROBE criteria. RESULTS: 43/576 (8%) BTC occurred: 37/43 (86%) on fluconazole (28 prophylaxis, median 200 mg/day). 21% BTC vs. 23% non-BTC presented severe sepsis/septic shock. Overall mortality was 34% vs. 32%. BTC was associated with gastrointestinal mucositis (multivariate OR 5.25, 95%CI 2.23-12.40, p < 0.001) and graft-versus-host-disease (6.25, 1.00-38.87, p = 0.05), immunosuppression (2.42, 1.03-5.68, p = 0.043), and parenteral nutrition (2.87, 1.44-5.71, p = 0.003). Non-albicans Candida were isolated in 58% BTC vs. 35% non-BTC (p = 0.005). 63% of 16 BTC occurring after 10-day fluconazole were non-susceptible (Candida glabrata, Candida krusei, Candida norvegensis) vs. 19% of 21 BTC (C. glabrata) following shorter exposure (7.10, 1.60-31.30, p = 0.007). Median fluconazole MIC was 4 mg/l vs. 0.25 mg/l (p < 0.001). Ten-day fluconazole exposure predicted non-susceptible BTC with 73% accuracy. CONCLUSIONS: Outcomes of BTC and non-BTC were similar. Fluconazole non-susceptible BTC occurred in three out of four cases after prolonged low-dose prophylaxis. This implies reassessment of prophylaxis duration and rapid de-escalation of empirical therapy in BTC after short fluconazole exposure.

[The treatment of tuberculosis]. / Die Behandlung der Tuberkulose.

The incidence of tuberculosis decreases. However, clinical cases frequently raise questions, mainly in the context of contact tracing or when antimicrobial resistance is suspected. Empiric standard treatment consists of rifampin, isoniazid, ethambutol and pyrazinamide. This initial regimen aims to reduce the number of pathogenic germs while the consolidation therapy should eradicate the remaining pathogens. Treatment duration and adherence are crucial for cure. For the treatment of latent tuberculosis the traditional 6 to 9 months isoniazid regimen is still the treatment of choice. In complex cases such as tuberculosis in immunocompromised patients or if resistant tuberculosis is suspected, patients should be referred to a specialized center.

Non-Seasonal Variation of Airborne Aspergillus Spore Concentration in a Hospital Building.

Nosocomial fungal infections are gaining increased attention from infectiologists. An adequate investigation into the levels of airborne Aspergillus and other fungal spores in hospital settings, under normal conditions, is largely unknown. We monitored airborne spore contamination in a Swiss hospital building in order to establish a seasonally-dependent base-line level. Air was sampled using an impaction technique, twice weekly, at six different locations over one year. Specimens were seeded in duplicate on Sabouraud agar plates. Grown colonies were identified to genus levels. The airborne Aspergillus spore concentration was constantly low throughout the whole year, at a median level of 2 spores/m³ (inter-quartile range = IQR 1-4), and displayed no seasonal dependency. The median concentration of other fungal spores was higher and showed a distinct seasonal variability with the ambient temperature change during the different seasons: 82 spores/m³ (IQR 26-126) in summer and 9 spores/m³ (IQR 6-15) in winter. The spore concentration varied considerably between the six sampling sites in the building (10 to 26 spores/m³). This variability may explain the variability of study results in the literature.

Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator.

BACKGROUND: In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada. METHODS: In our clinical cohort we included patients starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included patients in the British Columbia multiple sclerosis database (BCMS; data collection 1980-96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS patients with untreated progression modelled from BCMS patients using continuous Markov and multilevel models. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective. FINDINGS: 5610 patients starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS patients in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS patients had a mean follow-up of 5·1 years (SD 1·4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75·8% [95% CI 71·4-80·2]; multilevel model, 60·0% [56·6-63·4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58·5% [95% CI 54·2-62·8]; multilevel model, 57·1% [53·0-61·2]). INTERPRETATION: Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in patients with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible. FUNDING: Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme.

UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model.

OBJECTIVES: In 2002, the UK's National Institute for Health and Care Excellence concluded that the multiple sclerosis (MS) disease modifying therapies; interferon-ß and glatiramer acetate, were not cost effective over the short term but recognised that reducing disability over the longer term might dramatically improve the cost effectiveness. The UK Risk-sharing Scheme (RSS) was established to ensure cost-effective provision by prospectively collecting disability-related data from UK-treated patients with MS and comparing findings to a natural history (untreated) cohort. However, deficiencies were found in the originally selected untreated cohort and the resulting analytical approach. This study aims to identify a more suitable natural history cohort and to develop a robust analytical approach using the new cohort. DESIGN: The Scientific Advisory Group, recommended the British Columbia Multiple Sclerosis (BCMS) database, Canada, as providing a more suitable natural history comparator cohort. Transition probabilities were derived and different Markov models (discrete and continuous) with and without baseline covariates were applied. SETTING: MS clinics in Canada and the UK. PARTICIPANTS: From the BCMS database, 898 'untreated' patients with MS considered eligible for drug treatment based on the UK's Association of British Neurologists criteria. OUTCOME MEASURE: The predicted Expanded Disability Status Scale (EDSS) score was collected and assessed for goodness of fit when compared with actual outcome. RESULTS: The BCMS untreated cohort contributed 7335 EDSS scores over a median 6.4 years (6357 EDSS 'transitions' recorded at consecutive visits) during the period 1980-1995. A continuous Markov model with 'onset age' as a binary covariate was deemed the most suitable model for future RSS analysis. CONCLUSIONS: A new untreated MS cohort from British Columbia has been selected and will be modelled using a continuous Markov model with onset age as a baseline covariate. This approach will now be applied to the treated UK RSS MS cohort for future price adjustment calculations.

Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm.

BACKGROUND: Proadrenomedullin (ProADM) confers additional prognostic information to established clinical risk scores in lower respiratory tract infections (LRTI). We aimed to derive a practical algorithm combining the CURB65 score with ProADM-levels in patients with community-acquired pneumonia (CAP) and non-CAP-LRTI. METHODS: We used data of 1359 patients with LRTI enrolled in a multicenter study. We chose two ProADM cut-off values by assessing the association between ProADM levels and the risk of adverse events and mortality. A composite score (CURB65-A) was created combining CURB65 classes with ProADM cut-offs to further risk-stratify patients. RESULTS: CURB65 and ProADM predicted both adverse events and mortality similarly well in CAP and non-CAP-LRTI. The combined CURB65-A risk score provided better prediction of death and adverse events than the CURB65 score in the entire cohort and in CAP and non-CAP-LRTI patients. Within each CURB65 class, higher ProADM-levels were associated with an increased risk of adverse events and mortality. Overall, risk of adverse events (3.9%) and mortality (0.65%) was low for patients with CURB65 score 0-1 and ProADM ≤0.75 nmol/l (CURB65-A risk class I); intermediate (8.6% and 2.6%, respectively) for patients with CURB65 score of 2 and ProADM ≤1.5 nmol/l or CURB classes 0-1 and ProADM levels between 0.75-1.5 nmol/L (CURB65-A risk class II), and high (21.6% and 9.8%, respectively) for all other patients (CURB65-A risk class III). If outpatient treatment was recommended for CURB65-A risk class I and short hospitalization for CURB65-A risk class II, 17.9% and 40.8% of 1217 hospitalized patients could have received ambulatory treatment or a short hospitalization, respectively. CONCLUSIONS: The new CURB65-A risk score combining CURB65 risk classes with ProADM cut-off values accurately predicts adverse events and mortality in patients with CAP and non-CAP-LRTI. Additional prospective cohort or intervention studies need to validate this score and demonstrate its safety and efficacy for the management of patients with LRTI. TRIAL REGISTRATION: Procalcitonin-guided antibiotic therapy and hospitalisation in patients with lower respiratory tract infections: the prohosp study; isrctn.org Identifier: ISRCTN: ISRCTN95122877.

Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections.

INTRODUCTION: Measurement of prohormones representing different pathophysiological pathways could enhance risk stratification in patients with community-acquired pneumonia (CAP) and other lower respiratory tract infections (LRTI). METHODS: We assessed clinical parameters and five biomarkers, the precursor levels of adrenomedullin (ADM), endothelin-1 (ET1), atrial-natriuretic peptide (ANP), anti-diuretic hormone (copeptin), and procalcitonin in patients with LRTI and CAP enrolled in the multicenter ProHOSP study. We compared the prognostic accuracy of these biomarkers with the pneumonia severity index (PSI) and CURB65 (Confusion, Urea, Respiratory rate, Blood pressure, Age 65) score to predict serious complications defined as death, ICU admission and disease-specific complications using receiver operating curves (ROC) and reclassification methods. RESULTS: During the 30 days of follow-up, 134 serious complications occurred in 925 (14.5%) patients with CAP. Both PSI and CURB65 overestimated the observed mortality (X2 goodness of fit test: P = 0.003 and 0.01). ProADM or proET1 alone had stronger discriminatory powers than the PSI or CURB65 score or any of either score components to predict serious complications. Adding proADM alone (or all five biomarkers jointly) to the PSI and CURB65 scores, significantly increased the area under the curve (AUC) for PSI from 0.69 to 0.75, and for CURB65 from 0.66 to 0.73 (P < 0.001, for both scores). Reclassification methods also established highly significant improvement (P < 0.001) for models with biomarkers if clinical covariates were more flexibly adjusted for. The developed prediction models with biomarkers extrapolated well if evaluated in 434 patients with non-CAP LRTIs. CONCLUSIONS: Five biomarkers from distinct biologic pathways were strong and specific predictors for short-term adverse outcome and improved clinical risk scores in CAP and non-pneumonic LRTI. Intervention studies are warranted to show whether an improved risk prognostication with biomarkers translates into a better clinical management and superior allocation of health care resources. TRIAL REGISTRATION: NCT00350987.

Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial.

BACKGROUND: Guidelines recommend blood culture sampling from hospitalized patients with suspected community-acquired pneumonia (CAP). However, the yield of true-positive results is low. We investigated the benefit of procalcitonin (PCT) on hospital admission to predict blood culture positivity in CAP. METHODS: This was a prospective cohort study with a derivation and validation set including 925 patients with CAP who underwent blood culture sampling on hospital admission. RESULTS: A total of 73 (7.9%) patients had true bacteremia (43 of 463 in the derivation cohort, 30 of 462 in the validation cohort). The area under the receiver operating characteristics curve of PCT in the derivation and validation cohorts was similar (derivation cohort, 0.83; 95% CI, 0.78-0.89; validation cohort, 0.79; 95% CI, 0.72-0.88). Overall, PCT was a significantly better predictor for blood culture positivity than WBC count, C-reactive protein, and other clinical parameters. In multivariate regression analysis, only antibiotic pretreatment (adjusted odds ratio, 0.25; P < .05) and PCT serum levels (adjusted odds ratio, 3.72; P < .001) were independent predictors. Overall, a PCT cutoff of 0.1 microg/L would enable reduction of the total number of blood cultures by 12.6% and still identify 99% of the positive blood cultures. Similarly, 0.25 microg/L and 0.5 microg/L cutoffs would enable reduction of blood cultures by 37% and 52%, respectively, and still identify 96% and 88%, respectively, of positive blood cultures. CONCLUSIONS: Initial PCT level accurately predicted blood culture positivity in patients with CAP. PCT measurement has the potential to reduce the number of drawn blood cultures in the emergency department and to implement a more targeted allocation of limited health-care resources.

Multiple sclerosis risk sharing scheme: two year results of clinical cohort study with historical comparator.

OBJECTIVE: To generate evidence on the longer term cost effectiveness of disease modifying treatments in patients with relapsing-remitting multiple sclerosis. DESIGN: Prospective cohort study with historical comparator. SETTING: Specialist multiple sclerosis clinics in 70 centres in the United Kingdom. PARTICIPANTS: Patients with relapsing-remitting multiple sclerosis who started treatment from May 2002 to April 2005 under the UK risk sharing scheme. INTERVENTIONS: Treatment with interferon beta or glatiramer acetate in accordance with guidelines of the UK Association of British Neurologists. MAIN OUTCOME MEASURES: Observed utility weighted progression in disability at two years' follow-up assessed on the expanded disability status scale (EDSS) compared with that expected by applying the progression rates in a comparator dataset, modified for patients receiving treatment by multiplying by the hazard ratio derived separately for each disease modifying treatment from the randomised trials. RESULTS: In the primary per protocol analysis, progression in disability was worse than that predicted and worse than that in the untreated comparator dataset ("deviation score" of 113%; excess in mean disability status scale 0.28). In sensitivity analyses, however, the deviation score varied from -72% (using raw baseline disability status scale scores, rather than applying a "no improvement" algorithm) to 156% (imputing missing data for year two from progression rates for year one). CONCLUSIONS: It is too early to reach any conclusion about the cost effectiveness of disease modifying treatments from this first interim analysis. Important methodological issues, including the need for additional comparator datasets, the potential bias from missing data, and the impact of the "no improvement" rule, will need to be addressed and long term follow-up of all patients is essential to secure meaningful results. Future analyses of the cohort are likely to be more informative, not least because they will be less sensitive to short term fluctuations in disability.

Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial.

CONTEXT: In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs). OBJECTIVE: To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes. DESIGN, SETTING, AND PATIENTS: A multicenter, noninferiority, randomized controlled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008. INTERVENTION: Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based. MAIN OUTCOME MEASURES: Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics. RESULTS: The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n = 103] vs 18.9% [n = 130]; difference, -3.5%; 95% CI, -7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, -34.8%; 95% CI, -40.3% to -28.7%) and in the subgroups of patients with community-acquired pneumonia (n = 925, 7.2 vs 10.7 days; -32.4%; 95% CI, -37.6% to -26.9%), exacerbation of chronic obstructive pulmonary disease (n = 228, 2.5 vs 5.1 days; -50.4%; 95% CI, -64.0% to -34.0%), and acute bronchitis (n = 151, 1.0 vs 2.8 days; -65.0%; 95% CI, -84.7% to -37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n = 133] vs 28.1% [n = 193]; difference, -8.2%; 95% CI, -12.7% to -3.7%). CONCLUSION: In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN95122877.

Impact of an infection control program on the prevalence of nosocomial infections at a tertiary care center in Switzerland .

OBJECTIVE: To study the impact of a multimodal infection control program on the rate of nosocomial infections at a 550-bed tertiary care center. METHODS: Before and after the implementation of an infection control program, the rate of nosocomial infection was recorded in time-interval prevalence studies. Hand hygiene compliance was studied before and after the intervention. As a surrogate marker of compliance, the amount of alcohol-based hand rub consumed before the intervention was compared with the amount consumed after the intervention. The intervention included additional staff for infection control, repeated instructions for hand hygiene, new guidelines for preoperative antibiotic prophylaxis, and isolation of patients infected or colonized with multidrug-resistant bacteria. RESULTS: The rate of nosocomial infection decreased from approximately 11.7% to 6.8% in 2 years. The rate of hand hygiene compliance increased by 20.0%; it was 59.0% before the intervention and increased to 79.0% afterward. These results correlate with data on the consumption of alcohol-based hand rub, but not with data on the use of antibiotics. CONCLUSION: Within 2 years, a multimodal infection control program intervention such as this one may reduce the rate of nosocomial infection at a tertiary care center by more than one-third and improve both the quality of care and patient outcomes. It may also generate considerable savings. Therefore, such programs should be promoted not only by hospital epidemiologists but also by hospital administrators.

Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial.

BACKGROUND: Lower respiratory tract infections like acute bronchitis, exacerbated chronic obstructive pulmonary disease and community-acquired pneumonia are often unnecessarily treated with antibiotics, mainly because of physicians' difficulties to distinguish viral from bacterial cause and to estimate disease-severity. The goal of this trial is to compare medical outcomes, use of antibiotics and hospital resources in a strategy based on enforced evidence-based guidelines versus procalcitonin guided antibiotic therapy in patients with lower respiratory tract infections. METHODS AND DESIGN: We describe a prospective randomized controlled non-inferiority trial with an open intervention. We aim to randomize over a fixed recruitment period of 18 months a minimal number of 1002 patients from 6 hospitals in Switzerland. Patients must be >18 years of age with a lower respiratory tract infections <28 days of duration. Patients with no informed consent, not fluent in German, a previous hospital stay within 14 days, severe immunosuppression or chronic infection, intravenous drug use or a terminal condition are excluded. Randomization to either guidelines-enforced management or procalcitonin-guided antibiotic therapy is stratified by centre and type of lower respiratory tract infections. During hospitalization, all patients are reassessed at days 3, 5, 7 and at the day of discharge. After 30 and 180 days, structured phone interviews by blinded medical students are conducted. Depending on the randomization allocation, initiation and discontinuation of antibiotics is encouraged or discouraged based on evidence-based guidelines or procalcitonin cut off ranges, respectively. The primary endpoint is the risk of combined disease-specific failure after 30 days. Secondary outcomes are antibiotic exposure, side effects from antibiotics, rate and duration of hospitalization, time to clinical stability, disease activity scores and cost effectiveness. The study hypothesis is that procalcitonin-guidance is non-inferior (i.e., at worst a 7.5% higher combined failure rate) to the management with enforced guidelines, but is associated with a reduced total antibiotic use and length of hospital stay. DISCUSSION: Use of and prolonged exposure to antibiotics in lower respiratory tract infections is high. The proposed trial investigates whether procalcitonin-guidance may safely reduce antibiotic consumption along with reductions in hospitalization costs and antibiotic resistance. It will additionally generate insights for improved prognostic assessment of patients with lower respiratory tract infections. TRIAL REGISTRATION: ISRCTN95122877.

Stage-related outcome in twin-twin transfusion syndrome treated by fetoscopic laser coagulation.

OBJECTIVE: To assess perinatal outcome in monochorionic twin pregnancies according to different stages of severe mid-trimester twin-twin transfusion syndrome managed by fetoscopic laser coagulation of the placental vascular anastomoses. METHODS: In a prospective study fetoscopic laser therapy was performed in 200 consecutive pregnancies with severe mid-trimester twin-twin transfusion syndrome at a median gestational age of 20.7 weeks (range 15.9-25.3 weeks). Outcome data were analyzed for the whole group and separately for each stage according to the Quintero staging system. RESULTS: The overall survival rate was 71.5% (286/400), with survival of both twins in 59.5% (119/200) and survival of at least one of the twins in 83.5% (167/200). The median gestational age at delivery of liveborn neonates was 34.3 weeks (range 23.1-40.4 weeks). There was a significant trend toward reduced survival rates with increasing stage (P=.038). The percentage of pregnancies with survival of both fetuses was 75.9% (22/29) for stage I, 60.5% (49/81) for stage II, 53.8% (43/80) for stage III, and 50% (5/10) for stage IV. At least one of the twins survived in 93.1% (27/29) at stage I, 82.7% (67/81) at stage II, 82.5% (66/80) at stage III, and 70% (7/10) at stage IV. The overall survival rate for donor fetuses was 70.5% (141/200) and for recipient fetuses, 72.5% (145/200). CONCLUSION: These data show that laser therapy is an effective therapeutic option for all stages of severe twin-twin transfusion syndrome and provide information to counsel patients according to the stage of the syndrome.