Alternative Prophylaxis Research Articles

Probiotics for the prevention of pediatric antibiotic-associated diarrhea.

Probiotics for the prevention of pediatric antibiotic-associated diarrhea.

Cost-effectiveness of antibiotic prophylaxis for dental patients with prosthetic joints: Comparisons of antibiotic regimens for patients with total hip arthroplasty

BackgroundClinician uncertainty concerning the need for antibiotic prophylaxis to prevent prosthetic joint infection (PJI) after undergoing dental procedures persists. Improved understanding of the potential clinical and economic risks and benefits of antibiotic prophylaxis will help inform the debate and facilitate the continuing evolution of clinical management guidelines for dental patients with prosthetic joints. MethodsThe authors developed a Markov decision model to compare the lifetime cost-effectiveness of alternative antibiotic prophylaxis strategies for dental patients aged 65 years who had undergone total hip arthroplasty (THA). On the basis of the authors’ interpretation of previous recommendations from the American Dental Association and American Academy of Orthopaedic Surgeons, they compared the following strategies: no prophylaxis, prophylaxis for the first 2 years after arthroplasty, and lifetime prophylaxis. ResultsA strategy of foregoing antibiotic prophylaxis before dental visits was cost-effective and resulted in lower lifetime accumulated costs ($11,909) and higher accumulated quality-adjusted life years (QALYs) (12.375) when compared with alternative prophylaxis strategies. ConclusionsThe results of Markov decision modeling indicated that a no-antibiotic prophylaxis strategy was cost-effective for dental patients who had undergone THA. These results support the findings of case-control studies and the conclusions of an American Dental Association Council on Scientific Affairs report that questioned general recommendations for antibiotic prophylaxis before dental procedures. Practical ImplicationsThe results of cost-effectiveness decision modeling support the contention that routine antibiotic prophylaxis for dental patients with total joint arthroplasty should be reconsidered.

Anti-seizure prophylaxis in critically ill patients with traumatic brain injury in an intensive care unit.

The objectives of this prospective observational study were to determine the proportion of patients with traumatic brain injury who received effective anti-seizure prophylaxis. The study was conducted in a tertiary level ICU of a major trauma referral centre between February 2012 and August 2013. A total of 2361 patients were admitted to the ICU in this study period, of whom125 patients (index) with traumatic head injury were included in this study. The patients had a mean age of 45 years (SD=19), a mean score on the Glasgow Coma Scale of 9 (SD=4), a mean injury severity score of 27 (SD=13) and a mean APACHE III score of 55 (SD=27). Only 13.6 % (17 of 125) of patients were given anti-seizure prophylaxis and phenytoin levels were measured in 9.6% (12 of 125). Although all 12 patients achieved an effective concentration for phenytoin therapy (>40 µmol/l) after the loading dose, no patient had their target concentration consistently maintained in the recommended therapeutic range (40 to 80 µmol/l) throughout the seven-day monitoring period. There was wide fluctuation in phenytoin levels in the patients in this study. Twenty-two (18%) of the index patients had post-traumatic seizures, indicating a high prevalence for this study. Poor compliance with guidelines could possibly explain this phenomenon. Future studies are needed to look at the dosing and monitoring of phenytoin and/or alternative anti-seizure prophylaxis in patients with traumatic brain injury.

The efficacy and safety of sirolimus-based graft-versus-host disease prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials.

The efficacy and safety of sirolimus (SIR)-based graft-versus-host disease (GVHD) prophylaxis in patients who were subjected to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain to be clarified; this meta-analysis was conducted to evaluate these factors. Data from original research were obtained from PubMed, Embase, and Cochrane central register of controlled trials databases. Randomized controlled trials (RCTs) evaluating the efficacy of SIR-based prophylaxis in allo-HSCT were included. The risk ratio (RR), with a 95% confidence interval (CI), was used to pool data. The random effects model was used, irrespective of the presence or absence of heterogeneity. Five RCTs were included in the meta-analysis. SIR was observed to significantly decrease the incidence of Grade II to IV acute GVHD (aGVHD; RR, 0.65; 95% CI, 0.47-0.89). However, the incidence of Grade III to IV aGVHD and chronic GVHD was not decreased (RR, 0.91; 95% CI, 0.59-1.40; RR, 1.04; 95% CI, 0.88-1.23, respectively). An analysis of the toxic effects of SIR revealed that SIR effected a significant increase in the incidence of sinusoidal obstructive syndrome (RR, 2.24; 95% CI, 1.26-4.01), while that of thrombotic microangiopathy was not significantly increased (RR, 2.48; 95% CI, 0.87-7.06). Moreover, SIR did not improve event-free survival and overall survival (RR, 0.97; 95% CI, 0.85-1.10; and RR, 0.92; 95% CI, 0.82-1.02, respectively). This meta-analysis indicated that the SIR-based regimen is an effective and safe alternative prophylaxis strategy for GVHD.

Culture Directed Antibiotic Prophylaxis Reduces Post-Prostate Biopsy Infectious Complications in the Community: A “How-to” for Urologists in the Trenches

IntroductionThe rate of post-prostate biopsy infection is increasing. We noted this trend in our practice and began using prebiopsy rectal swab cultures to direct antibiotic prophylaxis. Clinical investigation has shown that culture directed antibiotic prophylaxis is effective. We report our methods and results as validation that culture directed antibiotic prophylaxis works in the community. MethodsWe retrospectively reviewed the charts of 686 consecutive patients who underwent transrectal prostate biopsy from March 2010 to April 2013. The electronic medical record was queried for the antibiotic prophylaxis used, rectal swab culture, post-biopsy infection, culture data and post-biopsy hospitalization if applicable. Prebiopsy rectal swab was incorporated into our practice in May 2012. Each patient received 3 days of fluoroquinolone prophylaxis or culture directed antibiotic prophylaxis. If antibiotic resistance to standard fluoroquinolone prophylaxis was identified, antibiotic prophylaxis was adjusted appropriately. ResultsOf 543 patients who received standard fluoroquinolone prophylaxis 17 (3.1%) had infectious complications. Eight patients were hospitalized for post-biopsy sepsis and 4 received outpatient treatment for urinary tract infection. A total of 143 patients underwent prebiopsy rectal swabs and received culture directed antibiotic prophylaxis. Compared to standard antibiotic prophylaxis no patient treated with culture directed antibiotic prophylaxis after a rectal swab had infectious complications (p = 0.03). However, 19.5% of the patients in this group had resistant bacteria requiring alternative antibiotic prophylaxis. ConclusionsA prebiopsy rectal swab to direct antibiotic prophylaxis decreased post-biopsy infectious complications in the community setting. The strategy is simple and it improves patient safety.

Recurrent Lower Urinary Tract Infections Have a Detrimental Effect on Patient Quality of Life: a Prospective, Observational Study.

IntroductionThis study investigated the effects of recurrent urinary tract infections (rUTI) and the impact of prophylaxis on rUTI and patients’ quality of life (QoL).MethodsAltogether, 575 patients affected by rUTI were included in a 6-month observational study. QoL was assessed using the Hospital Anxiety and Depression (HAD) and the Leicester scales. Statistical analyses were performed using SAS® Version 8.2 software (SAS Institute Inc., Cary, NC, USA). The significance level was set at 5%. Spearman correlation was used to assess the degree of correlation between infectious episodes and HAD and Leicester scores. For each parameter, the comparison between Day 0 and Day 180 was performed using Wilcoxon signed-rank test for quantitative data.ResultsIn total, 61.9% of patients suffering from rUTI exhibited some degree of depression at baseline (Day 0). Alternative oral non-antimicrobial prophylactic treatment for rUTI [Escherichia coli lyophilized bacterial lysate (OM-89)] was administered to 94.4% of patients (1 capsule a day for 90 days), followed by a 3-month treatment-free period. At the end of the study (Day 180), the mean number of UTI decreased by 59.3% (P ≤ 0.0001), the total HAD score decreased by 32.1% (P ≤ 0.0001), and the mean Leicester score decreased by 44.0% (P ≤ 0.0001) from baseline. There was a correlation trend between the reduction in the numbers of UTI at the end of the study compared to the 6 months prior to study entry and the reduction in the anxiety, depression, total HAD scores, activity, feeling, and total Leicester scores registered from Day 0 to Day 180, suggesting a lessening of emotional problems, and social and functional handicaps with decreasing UTI incidence.ConclusionsThis study showed that rUTI had a negative impact on patients’ QoL and that effective alternative prophylaxis significantly improved their QoL.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0054-6) contains supplementary material, which is available to authorized users.

Non-Myeloablative Conditioning Targeting Host Immunosuppression Is Successful in Matched Sibling Donor Stem Cell Transplantation for Hemoglobinopathies in Children

▪Background: Myeloablative hematopoietic cell transplantation (HCT) provides a cure for children with hemoglobinopathies, but transplant related early and late morbidity remains a challenge. Toxicities associated with myeloablative chemotherapy include early complications such as mucositis, hemorrhagic cystitis, seizures, and hepatic injury. Late effects such as infertility and compromised linear growth impair long-term quality of life, often decreasing enthusiasm for the procedure. Reduced intensity preparative regimens are especially attractive in children with non-malignant disorders to mitigate these toxicities but have been associated with increased risk of graft rejection. The primary objective of this study was to determine the toxicity and efficacy of a non-myeloablative preparative regimen using alemtuzumab, fludarabine, and melphalan followed by HCT from HLA matched related donors (MRD) in children with hemoglobinopathies.Methods: Following institutional review board approval, and parent and/or patient consent, participants were enrolled at 18 centers. Children < 21 years of age with severe sickle cell disease (SCD) manifestations, or transfusion dependent (> 8 red blood cell transfusions per year) thalassemia with a MRD and a performance status > 40 were eligible for inclusion. The preparative regimen included alemtuzumab (total dose 48 mg) IV (between days –22 and –19), fludarabine (30 mg/m2/day) (days –8 to –4) and melphalan (140 mg/m2) on day -3. Graft versus host disease (GVHD) prophylaxis included a calcineurin inhibitor (tapered after day 100, and methotrexate (7.5 mg/m2 on days 1, 3 and 6) or mycophenolate mofetil. Five patients also received methylprednisone (1 mg/kg/day) between days 1 and 28; this practice was discontinued in 2007.Results: A total of 52 children (43 with SCD and 9 with thalassemia), median age 11 years (range, 10m - 20y) underwent HCT between March 2003 and July 2014. Of these, 46 received bone marrow, 5 received marrow and cord blood (CB), and 1 received CB alone. Median follow up was 35.5 months (range, 3 – 136). Forty-nine children were alive at last follow up (Figure 1); 48 were symptom-free; one CB recipient had disease recurrence following graft rejection and successfully underwent a 2nd HCT. No hepatic veno-occlusive disease was noted. Three deaths 6, 11 and 21 months post HCT were from GVHD related causes [bronchiolitis obliterans (n=1); infection with GVHD (n=2)]. The cumulative incidence of graft failure and transplant related mortality was 1.9% and 5.7% respectively. The mean time to engraftment of neutrophils (ANC >500/cu mm) and platelets (>50,000/cu mm) was 13.0 (range 5-21) and 25.9 (range 8-120) days respectively. Three patients had neurologic toxicity (seizures/PRES) post HCT. At the time of last follow up, 35 patients (67%) were complete donor chimera (>90% donor) and 16 (31%) were mixed chimera (28-89% donor). Acute GVHD (grade 1-3) was noted in 30.8%. Four had grade I, 6 had grade II, and 6 had grade III GVHD. No patient developed grade IV aGVHD. Chronic GVHD was noted in 13%. Of 43 patients that were alive without disease and >6 months post HSCT, 38 had successfully discontinued all immune suppression and maintained donor chimerism post withdrawal. Immune reconstitution was robust by the end of the first year post transplant; infectious complications (23 of 30 CMV+ recipients had reactivation) were noted primarily in the first 3 months post HSCT.Conclusions: Children with hemoglobinopathies undergoing MRD HCT tolerated this non-myeloablative preparative regimen well, with minimal early toxicities. The event-free survival rate was comparable to those achieved with myeloablative regimens. Withdrawing immunosuppression was not associated with graft loss or recurrent GVHD. GVHD complications resulted in a low mortality rate. Alternative GVHD prophylaxis may further improve event-free survival. No gonadal toxicity (determined by hormone levels) has been identified to date in 15 HCT recipients of pubertal age (>13 years). Follow up however is early and in progress to determine long-term toxicities. These results support consideration of reduced intensity conditioning regimens for HCT in children with hemoglobinopathies as an alternative to standard myeloablative regimens. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Evaluation of the expression of I-FABP and L-FABP in a necrotizing enterocolitis model after the use of Lactobacillus acidophilus

Background/purposeNecrotizing enterocolitis (NEC) is a severe intestinal disease that primarily affects premature babies, leading to high mortality and morbidity. Probiotics represent an important alternative prophylaxis for NEC but its mechanism of action is poorly understood. Moreover, intestinal and liver-type fatty acid-binding proteins (I-FABP and L-FABP) may be utilized because markers of intestinal injury, including NEC. We aimed to evaluate the protection induced by the Lactobacillus acidophilus on the intestines of newborn rats submitted to experimental NEC using I-FABP and L-FABP as biomarkers. MethodsSprague–Dawley newborn rats were divided into three groups: (1) C (control)—breast-fed; (2) NEC—subjected to NEC protocol and (3) NECP—NEC+probiotic. Morphometric, intestinal lesion, immunohistochemistry and Western blotting analysis were performed. Statistical significant differences were considered when p<0.05. ResultsIntestinal weight was lower in NEC and NECP compared to C (p<0.05). Intestinal injury was lower in NECP compared to NEC. Prophylactic probiotic recovered mucosa and muscular layers' thickness to C levels (p<0.05). I-FABP and L-FABP expressions in NECP showed intermediate values between C and NEC. ConclusionL. acidophilus had a protective effect on the development of NEC and FABPs could demonstrate the degree of tissular damage of the intestine.

Using value-of-information methods when the disease is rare and the treatment is expensive--the example of hemophilia A.

Hemophilia A is a rare, sex-linked genetic disorder treated with intravenous administration of factor VIII (FVIII) to prevent bleeding; however, approaches vary across and within countries. Value-of-information (VOI) methods identify situations in which the cost-benefit evidence is sufficient to adopt one treatment strategy over another; when the evidence is insufficient, VOI methods provide the optimal sample size for additional research. The objective of the study was to use VOI methods in a cost-benefit decision context to evaluate the current evidence in support of using (1) alternate day prophylaxis (AP), (2) tailored prophylaxis (TP) or (3) on-demand treatment (OD) with FVIII to prevent arthropathy in children with severe hemophilia A. To apply VOI methods, several parameters such as incidence, time horizon for the decision, costs, and threshold values to avoid MRI-detected joint damage or arthropathy were defined. Two baseline threshold values of willingness to pay for avoiding arthropathy--$200,000 and $400,000--were selected for comparing the treatment strategies. For threshold values < $200,000, OD had a higher expected net benefit than either prophylaxis strategy, and the evidence was sufficient for its adoption. For threshold values > $400,000 prophylaxis strategies had higher expected net benefit; however, a new trial with 38 patients per arm was needed to compare AP and TP, yielding an expected net gain of over $17 million. In sensitivity analyses, the results were robust to assumptions regarding discount rate, trial fixed and variable costs, enrollment fraction, and the time horizon. In rare diseases, evidence is often scarce and insufficient for decision making. In considering the funding of new research and patient reimbursement in rare diseases, VOI methodology may provide more relevant determinations of the value and costs of additional research, compared to standard frequentist methods.

Effect of preoperative biliary drainage for obstructive jaundice on postoperative course after pancreaticoduodenectomy

s / Pancreatolog S108 Aims: Definition of an alternative prophylaxis targeted on bile cultures in pancreatic surgery and validation of SSIs incidence. Patients & methods: Between Jan-2010 and Oct-2013 we performed 222 consecutive pancreatic resections with bile contamination (203 pancreaticoduodenectomies, 19 total pancreatectomies). We routinely performed culture on intra-operative bile samples and prospectively recorded SSIs. Analyzing antimicrobial susceptibility of detected germs, we introduced from Mar-2013 ampicillin-sulbactam as alternative to cefazolin for perioperative prophylaxis; we therefore realized a comparison between patients receiving standard (n1⁄4170) and new (n1⁄452) schedule. Results: Analyzing the standard group, 56% of patients had positive bile cultures; 49% of microbes belonged to Enterococcus Spp. 47% of patients had a preoperative biliary stent: it was strongly associated with bile infection (100% vs 17%, p<0,001); bile infection was associated with higher morbidity in patients with (72% vs 56%, p1⁄40,037) or without stent (87% vs 56%, p1⁄40,026), as well as with higher SSIs (63% vs 37%, p1⁄40,113). 49,5% of infected bile samples harbored cefazolin-resistant microbes: in these patients postoperative global SSIs were higher (71% vs 30%, p1⁄40,023) as well as superficial, deep and organ/space-SSIs. Since we administered ampicillin-sulbactam perioperative prophylaxis, we observed a significant decrease of superficial (20,6% vs 3,8%, p1⁄40,005) and deep (8,8% vs 0, p1⁄40.025) SSIs; we noted no difference in organ/space-SSIs. Conclusion: Bile infection leads to a significant increase of postoperative morbidity in pancreatic surgery. Bile-culture targeted prophylaxis seems effective in reducing SSIs.

Cefpodoxime for Antimicrobial Prophylaxis in Neutropenia: A Retrospective Case Series

BackgroundAntimicrobial prophylaxis in select neutropenic patients has reduced fever, infection rates, hospital length of stay, and hospitalization rates. Guidelines from the Infectious Diseases Society of America recommend the consideration of prophylaxis with a fluoroquinolone in patients at high risk for infection after chemotherapy. The use of fluoroquinolones has been associated with many adverse events, and there is limited evidence on alternative antimicrobial prophylaxis in patients intolerant of fluoroquinolones. ObjectivesOur study describes a single-center experience of cefpodoxime as an alternative to fluoroquinolones for antibacterial prophylaxis during neutropenia after chemotherapy and represents a retrospective evaluation of an oral cephalosporin in adult patients for this purpose. MethodsThis retrospective case series analyzed data from the electronic medical records of 41 patients having hematologic malignancies and given cefpodoxime for neutropenic prophylaxis. ResultsThe rate of febrile neutropenia was 85%, with 60% culture-positive infections. Gram-positive organisms were identified in 52% of positive cultures, and gram-negative organisms represented 40% of positive cultures. Antimicrobial resistance to guideline-recommended empiric treatment regimens was not seen in breakthrough infections. ConclusionsCefpodoxime can be utilized for prophylaxis, without adversely affecting resistance to broad-spectrum agents, and maintains a high level of appropriateness of guideline-recommended empiric regimens. This study of cefpodoxime prophylaxis in adult patients intolerant to fluoroquinolones adds to the literature of potential alternative agents for prophylaxis in neutropenic patients.

Role of contact tracing and prevention strategies in the interruption of leprosy transmission

The global prevalence of leprosy has declined from 5.2 million in the 1980 s to 200,000 today. However, the new case detection rate remains high: over the last 8 years, around 220,000-250,000 people have been diagnosed with leprosy each year. In June 2013, an international meeting was organised by the Novartis Foundation for Sustainable Development in Geneva, Switzerland,2 with the objective of discussing the feasibility of interrupting the transmission of leprosy. The group of physicians, epidemiologists and public health professionals concluded that a successful programme would require early diagnosis and prompt multidrug therapy (MDT) for all patients, tracing and post-exposure prophylaxis (PEP) for contacts of patients newly diagnosed with leprosy, improvements in diagnostic tools, as well as strict epidemiological surveillance and response systems to monitor progress. As a follow-up, a second expert group meeting was convened by the Novartis Foundation in January 2014 in Zurich, Switzerland, with the objective of reviewing the evidence for chemoprophylaxis in contacts and high-risk communities. The meeting also considered the definitions of 'contacts' and 'contact tracing', discussed alternative prophylaxis regimens, preliminary findings of operational pilot projects on PEP in Indonesia, as well as the development of diagnostic tools, and identified the priority questions for operational research in leprosy transmission. The meeting outlined how contact tracing and chemoprophylaxis programmes can be implemented to interrupt leprosy transmission. The expert panel reached the following conclusions: Chemoprophylaxis with single-dose rifampicin (SDR) is efficacious in reducing the risk of developing leprosy, although the protective effect appears to be smaller in contacts closer to the index patient than in more distant contacts.3 SDR can be targeted to contacts or implemented as community mass prophylaxis in certain circumstances; the preferred approach depends on local factors, such as the case detection rate, the level of community stigma against leprosy, and the degree of access to healthcare for patients and contacts. Alternative prophylaxis regimens and the role of post-exposure immunoprophylaxis need to be further investigated. Contact tracing combined with PEP across very diverse settings offers protection rates similar to those reported in controlled trials. For high-incidence pockets ('hotspots') or remote or confined high-incidence populations ('hotpops'), blanket administration of PEP may be a better option. Implementation of contact-tracing programmes is feasible and cost-effective, particularly in high-risk groups, but it should be integrated into local healthcare services to ensure their long-term sustainability. Funding and support must be maintained after an initial pilot has finished. New programmes for contact tracing need effective surveillance systems to enable appropriate follow-up and outcome evaluation. The Novartis Foundation and Netherlands Leprosy Relief (NLR) are currently developing and implementing a large international programme to demonstrate the feasibility, acceptability, cost-effectiveness and real-world efficacy of PEP as a strategy to interrupt leprosy transmission, in six pilot projects in Asia, Africa and South America. These new pilot projects will be developed together with the local health authorities, healthcare workers, communities and patients, in order to create local ownership from the outset. The pilots should aim to be scalable and sustainable, and should therefore include an objective outcome assessment. Local ownership ensures that locally appropriate language and definitions of contacts are used in each of the pilots. A test to identify subclinical disease and distinguish M. leprae exposure from infection would facilitate early and appropriate therapy (with PEP or MDT). The identification and validation of new, sensitive biomarkers for M. leprae infection and exposure may allow better targeting of PEP to those contacts at highest risk of developing leprosy.

Frequent Ineffectiveness of Cefazolin as Perioperative Prophylaxis in Pancreatic Surgery

Context Cefazolin is widely accepted as routine antimicrobial prophylaxis in hepatobiliary and pancreatic surgery. Microbial resistance to this drug is rapidly increasing, nullifying the expected beneficial effects of its administration and exposing patients to potentially severe infective complications. Objective Analysis of bile culture results and comparison with postoperative outcomes in patients undergoing pancreatic surgery in a referral centre; definition of an alternative prophylaxis schedule. Methods Between Jan 2010 and Jan 2013 we performed 170 consecutive major resections requiring abdominal bile exposure, of which 156 pancreaticoduodenectomies and 14 total pancreatectomies. We routinely performed culture on bile samples obtained intraoperatively and on drain liquid samples taken on fifth postoperative day. We then prospectively recorded data about postoperative septic complications and analyzed them consulting our referral infectious disease specialist. Results Among the 170 patients, 95 (56%) had positive bile cultures, of which 73 (43%) with multiple microbes. The great majority of microbes obtained belonged to Enterococcus Spp . ( E. Faecalis 29%, E. Facium 18%), while other well represented germs were E. Coli (18%), Enterobacter Spp . (18%), Klebsiella Spp . (12%). Eighty patients (47%) received preoperative biliary stenting, which resulted strongly associated with bile infection (100% vs . 17%, P<0.001). Bile infection was associated with higher morbidity both in patient with stent (72% vs . 56%, P=0.037), and without stent (87% vs . 56%, P=0.026). Forty-seven (49%) of infected bile samples harbored microbes resistant to cefazolin; in these patient postoperative infective complication rate was significantly higher (61% v s . 39%, P=0.016) than in patients that did not harbor. The rate of cefazolin resistant microbe identification was even higher on drain samples (58%), which shared microbes with previous bile sample in 80% of cases, even though it was not associated with higher morbidity. Analyzing antimicrobial susceptibility of these germs we identify the association ampicillin-sulbactam as a new possible drug for perioperative prophylaxis. Conclusions Infective complications in pancreatic surgery could lead to severe consequences. Adequate antimicrobial prophylaxis, selected using epidemiological evidence from patients samples, is mandatory. Ampicillin-sulbactam could be a viable alternative to cefazolin in surgical procedures involving abdomen bile exposure, although further studies are necessary to validate this drug benefits.

Preventive Strategies for Atrial Fibrillation After Cardiac Surgery in Nordic Countries

Atrial fibrillation is a common arrhythmia after cardiac surgery. It increases morbidity, length of hospital stay, and costs of operative treatment. Beta-blockers, sotalol, amiodarone, corticosteroids, and biatrial pacing have been shown to be efficient in the prevention of postoperative atrial fibrillation. The aim of this study was to find out how widely different prophylactic strategies for postoperative atrial fibrillation are used in Scandinavian countries. An online link for a questionnaire was emailed to (214) cardiac surgeons in Finland, Sweden, Norway, Denmark, and Estonia to assess the use of prophylactic methods for postoperative atrial fibrillation. A total of 97 surgeons responded to the survey. Oral beta-blockers were routinely used for atrial fibrillation prophylaxis by 62% of responders. The main reasons for nonuse of beta-blockers were that responders were unconvinced of the evidence of benefit or they preferred some alternative prophylaxis. Intravenous beta-blockers were used frequently by 6% of responders. Amiodarone was used for prophylaxis by 18% of responders. Nonusers were unconvinced of its efficacy, were afraid of its complications, or found its use too cumbersome. Other prophylactic atrial fibrillation strategies that were used are as follows: sotalol by 2%, magnesium by 17%, corticosteroids by 1%, and atrial pacing by 11% of respondents. There is still widely varying implementation of strategies for atrial fibrillation prophylaxis among Scandinavian cardiac surgeons. Lack of confidence in the efficacy of these approaches is the main rationale for nonimplementation.

Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children

Antibiotics are widely prescribed; however they can cause disturbances in gastrointestinal flora which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live organisms thought to balance the gastrointestinal flora. The primary objectives were to assess the efficacy and safety of probiotics for preventing Clostridium difficile-associated diarrhea (CDAD) or C. difficile infection in adults and children. On February 21, 2013 we searched PubMed (1966-2013), EMBASE (1966-2013), Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1), CINAHL (1982-2013), AMED (1985-2013), and ISI Web of Science. Additionally, we conducted an extensive grey literature search including contact with industry representatives. Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion. Two authors independently and in duplicate extracted data and assessed risk of bias using pre-constructed, and piloted, data extraction forms. Any disagreements were resolved by a third adjudicator.For articles published in abstract form only, further information was sought by contacting principal authors. The primary outcome was the incidence of CDAD. Secondary outcomes included the incidence of C. difficile infection, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the relative risk and corresponding 95% confidence interval (95% CI). Continuous outcomes (e.g. length of hospital) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias.The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria. A total of 1871 studies were identified with 31 (4492 participants) meeting eligibility requirements for our review. Overall 11 studies were rated as a high risk of bias due mostly to missing outcome data. A complete case analysis (i.e. participants who completed the study) of those trials investigating CDAD (23 trials, 4213 participants) suggests that probiotics significantly reduce this risk by 64%. The incidence of CDAD was 2.0% in the probiotic group compared to 5.5% in the placebo or no treatment control group (RR 0.36; 95% CI 0.26 to 0.51). Sixteen of 23 trials had missing CDAD data ranging from 5% to 45%. These results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and were similar whether considering trials in adults versus children, lower versus higher doses, different probiotic species, or higher versus lower risk of bias. Our judgment is that the overall evidence warrants moderate confidence in this large relative risk reduction. We downgraded the overall quality of evidence for CDAD to 'moderate' due to imprecision. There were few events (154) and the calculated optimal information size (n = 8218) was more than the total sample size. With respect to the incidence of C. difficile infection, a secondary outcome, pooled complete case results from 13 trials (961 participants) did not show a statistically significant reduction. The incidence of C. difficile infection was 12.6% in the probiotics group compared to 12.7% in the placebo or no treatment control group (RR 0.89; 95% CI 0.64 to 1.24). Adverse events were assessed in 26 studies (3964 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 20% (RR 0.80; 95% CI 0.68 to 0.95). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. For the short-term use of probiotics in patients that are not immunocompromised or severely debilitated, we consider the strength of this evidence to be moderate. Based on this systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients, moderate quality evidence suggests that probiotics are both safe and effective for preventing Clostridium difficile-associated diarrhea.

Headache in Children: Update on Complementary Treatments

Complementary and alternative medicine (CAM) is widely used by both physicians and patients with primary headache syndromes. Despite a considerable number of articles addressing CAM in primary headache syndromes, the overall evidence for CAM is still poor. The aim of this review was to give an overview of the current evidence of the main alternative therapies used in the treatment of primary headache syndromes of childhood. MEDLINE and Cochrane Library were systematically searched for articles dealing with complementary and alternative treatment or prophylaxis of headache and migraine published within the past 20 years.

The Effectiveness and Mechanism ofToona sinensisExtract Inhibit Attachment of Pandemic Influenza A (H1N1) Virus

TSL-1 is a fraction of the aqueous extract from the tender leaf of Toona sinensis Roem, a nutritious vegetable. The pandemic influenza A (H1N1) virus is a recently described, rapidly contagious respiratory pathogen which can cause acute respiratory distress syndrome (ARDS) and poses a major public health threat. In this study, we found that TSL-1 inhibited viral yields on MDCK plaque formation by pandemic influenza A (H1N1) virus on infected A549 cells with high selectivity index. Meanwhile, TSL-1 also suppressed viral genome loads in infected A549 cells, quantified by qRT-PCR. This study further demonstrated that TSL-1 inhibited pandemic influenza A (H1N1) virus activity through preventing attachment of A549 cells but not penetration. TSL-1 inhibited viral attachment through significant downregulation of adhesion molecules and chemokines (VCAM-1, ICAM-1, E-selectin, IL-8, and fractalkine) compared to Amantadine. Our results suggest that TSL-1 may be used as an alternative treatment and prophylaxis against pandemic influenza A (H1N1) virus.

Risk of cytomegalovirus disease in high‐risk liver transplant recipients on valganciclovir prophylaxis: A systematic review and meta‐analysis

Valganciclovir (VGC) was approved by the Food and Drug Administration in 2004 as cytomegalovirus (CMV) prophylaxis except for liver transplant recipients because of their high incidence of CMV disease with this drug. However, surveys have shown its common off-label use for CMV prophylaxis in liver transplant recipients. We aimed to evaluate the risk of CMV disease with VGC prophylaxis in liver transplant recipients. All studies that evaluated liver transplant recipients and used VGC (900 or 450 mg daily) for the prevention of CMV disease were included. Five controlled studies (n = 483) were pooled with a random effects model; five single-arm studies (n = 380) were pooled for the prevalence rate of CMV disease. The risk of CMV disease with VGC versus ganciclovir was 1.81 [95% confidence interval (CI) = 1.00-3.29, P = 0.05, I(2) = 0%]. For high-risk (donor-positive/recipient-negative) patients, the risk of CMV disease was 1.96 (95% CI = 1.05-3.67, P = 0.035, I(2) = 0%). The risk of CMV disease remained significant with 900 mg of VGC daily (P = 0.04) but not with 450 mg of VGC daily (P = 0.76). The risk of leukopenia with VGC was 1.87 (95% CI = 1.03-3.37, P = 0.04, I(2) = 0%). In single-arm trials, the overall CMV disease rate was 12% (95% CI = 9%-16%, P < 0.001), and the rate for high-risk patients was 20% (95% CI = 10%-38%, P = 0.002). In conclusion, 900 mg of VGC daily may not be safe as CMV prophylaxis in high-risk liver transplant recipients because of the significant 2-fold increase in the risk of CMV disease and the 1.9-fold increase in the risk of leukopenia. Alternative CMV prophylaxis should be used for liver transplant recipients.

Distinct IFN-Gamma Dependent Effect of the TLR5 Agonist, Flagellin On NK and CD4+ T Cell Immunity Against CMV

AbstractAbstract 255 Background:Opportunistic CMV infection remains a major clinical complication in allogeneic BMT (allo-BMT) recipients. We previously published that peri-transplant treatment of highly purified flagellin, a TLR5 agonist extracted from S. typhimurium reduced GvHD in lethally irradiated allo-BMT recipients by reducing early activation and proliferation of donor T cells. Flagellin-treated recipients had enhanced lymphoid immune reconstitution and were protected from lethal MCMV infection. CMV initiates innate immunity through the activation of Toll-like receptors (TLR) 9, 3 and 2 but direct enhancement of anti-CMV immunity through TLR5 has not been studied. Methods:To further explore the effects of a TLR5 agonist on anti-CMV immunity, we infected flagellin-treated C57BL/6 (B6), TLR5KO and Myd88KO mice (B6 background) with sub lethal dose (1×105pfu/mouse i.p) of MCMV. Anti-CMV immunity of NK and T-cells were determined by measuring surface activation markers on the NK and T-cells. Flagellin-treated and MCMV infected IL-12KO, IFN-γRKO and IDO KO mice were used to study the role of IL-12, IFN-γ and IDO on anti-CMV immunity. The relationship between the MCMV lethality and flagellin signaling in hematopoietic or epithelial tissues expressing TLR5 was further investigated by generating radiation chimeras, using WT mice engrafted with TLR5 KO bone marrow (BM) and TLR5 KO mice engrafted with WT B6 BM. Chimeric recipients with WT or TLR5KO hematopoietic cells (or the reverse) were then treated with flagellin or PBS and infected with a sub lethal dose of MCMV infection. Results:Without MCMV infection, flagellin treatment significantly increased numbers of NK cells (p= 0.001) and KLRG1+ NK cells (p=0.009) in WT B6 mice compared with the PBS-treated control mice. Following MCMV infection (day 3), there were significantly increased numbers of splenic NK cells (p= 0.01) and KLRG1+ NK cells (p=0.0008) in flagellin-treated mice compared with the control mice. Flagellin-treatment also enhanced viral clearance, tending to decrease liver viral loads in WT B6 mice. In contrast, MCMV-infected and flagellin-treated TLR5 KO or Myd88KO mice had significantly increased liver viral loads (p=00001) compared with the flagellin- and PBS-treated B6 mice on day 3 post MCMV infection. While flagellin-treatment increased the numbers and activation status of NK cells, it decreased the numbers of activated (CD69+, ICOS+ and KLRG1+) CD4+ T cells on day 3 post MCMV infection. On day 10 post MCMV infection, enhanced numbers of splenic CD8+ T cells and CMV-specific tetramer+ CD8+ T cells (p<0.05) were detected in flagellin-treated mice compared with controls. The numbers of splenic CD4+ T cells increased >2 fold (p= 0.008) associated with significantly increased numbers of splenic CD4+CD25+ Foxp3+ regulatory T cells (p<0.05) on day 10 post MCMV infection in flagellin-treated mice compared with the control mice. Flagellin-induced anti-CMV immunity required IFN-γ signaling as flagellin-treated IFN-γRKO mice had markedly increased susceptibility to MCMV infection whereas flagellin-treated IL-12 KO and IDO KO mice had significantly reduced liver viral loads compared to the PBS-treated IL-12 KO and IDO KO mice on day 10 post MCMV infection. To explore interaction of flagellin with TLR5+ host hematopoietic cells and TLR5+host gut epithelium on CMV immunity, we next infected radiation chimeras expressing either TLR5 on hematopoietic cells or on gut epithelium with sub lethal i.p dose of MCMV. Flagellin-treated TLR5 KO BM → B6 radiation chimeras (TLR5+ host epithelium) had increased mortality compared with other groups following MCMV infection indicating that TLR5+ hematopoietic cells are required for protective immunity against CMV infection.In summary, flagellin caused selective early increased activation of NK cells and reduced activation of CD4+ T cells in presence of MCMV infection. The protective effect of flagellin on anti-CMV immune responses are IFN-γ dependent but independent of IL-12 and IDO. The TLR5+ hematopoietic cells are required for the protective immunity against CMV infection. These data suggest the clinical importance of flagellin in modulating both innate and adaptive immunity against CMV infection and also as an alternative GvHD prophylaxis in allo-BMT recipients. Disclosures:No relevant conflicts of interest to declare.

Higher Infused Cell Dose Is Associated with a Decreased Risk of Invasive Fungal Infections After Allogeneic Hematopoietic Stem Cell Transplantation

Abstract 4134Invasive fungal infections/disease (IFI/IFD) are a major cause of morbidity and mortality after hematopoietic stem cell transplants (HCT), but their incidence and risk factors are not well defined. We performed a retrospective review of 270 consecutive adults (152 M/118 F), median age 53 (18–75) years, with hematologic malignancy receiving allogeneic HCT at Massachusetts General Hospital between 2000 to 2010 to determine the incidence, risk factors and outcomes of patients that developed IFD. All patients received antifungal prophylaxis from the start of conditioning until Day +100; 90% received fluconazole 400 mg daily. We defined IFD using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, defining proven cases as evidence of fungal elements in a sterile tissue, and probable as presence of fungal elements in non sterile tissue or positive Galactomannan antigen or β-D-Glucan test in patients with clinical features suggestive of IFI. Diagnoses were Acute Myeloid Leukemia (34%), Non Hodgkin’s Lymphoma (24%), Myelodysplastic syndrome (15%), Acute Lymphoblastic Leukemia (8%), Chronic Lymphocytic Leukemia (5%), Myeloproliferative disorders, Hodgkin Lymphoma and Multiple Myeloma (4% each), and others (2%). 15% had a prior autologous transplant. Conditioning included reduced intensity (64%) or myeloablative (36%) regimens. Donor source was fully HLA matched (MRD) in 60%, matched unrelated (MUD) in 20%, Haploidentical in 12% and Cord Blood in 8%. 41% received ATG based aGVHD prophylaxis vs non ATG based in 59%. 11% were diabetic, while 6% had a history of IFD prior to transplant. 55% received systemic steroids for GVHD and 34% received TPN during transplant course. Median follow up was 28 (1.0–141.0) months. 49 distinct episodes of IFI were observed in 40 subjects (15%). Aspergillus spp (47%) was most frequently encountered, followed by Candida spp (43%). Mucor was isolated in 1 case. Among the Candida spp, the majority (52%) were non albicans- Candida glabrata (8) vs 1 each of Candida krusei, Candida tropicalis and Candida parapsilosis. Most frequently infected site was the lungs (69%), followed by the blood stream and paranasal sinuses (14% each), and GI tract (4%). Spleen (hepatosplenic candidiasis), kidneys and brain were affected in 1 patient each. In 6%, involvement of both the lungs and sinuses was observed. The estimated probability of early IFD (within 100 days post transplant) was 7%. Patients and transplant factors, including age, diagnosis, prior autologous transplant, type of conditioning regimen, type of aGVHD prophylaxis, donor type, CD34+ cell dose infused, history of diabetes or prior IFD, systemic use of steroids for GVHD and TPN administration, were examined to determine risk factors for developing IFD. In multivariable analysis, haploidentical donor transplants (HR 3.48, 95% CI 1.35–8.99, p=0.01) and the development of Grade III and IV aGVHD (HR 3.32, 95% CI 1.23–9.01, p=0.02) were risk factors for the development of IFD. Conversely, higher CD34+ cell dose infused was associated with a lower risk of IFD (HR 0.80, 95% CI 0.68–0.94, p=0.01, per 1×10⋀6 cells/kg increase). The overall mortality (OM) of patients with IFD was 41%. A higher non-relapse mortality (NRM) was observed for patients with IFD as compared to patients without IFD, 55% vs 18% (HR 3.76, 95% CI 2.03–6.97, p<0.001). In multivariable analysis, accounting for CD34+ cell count, donor type and Grade III-IV aGVHD, the effect of IFI on NRM remained significant (HR 3.32, 95% CI 1.65–6.67, p=0.001). Patients with IFD had lower overall survival (OS), 16 months as opposed to 50 months for patients without IFD. In summary, 1) The risk of IFD after allogeneic HCT was 15%; 2) Patients with IFD have a high mortality after allogeneic HCT; 3) Haploidentical donor type and development of Grades III-IV GVHD are risk factors for IFD; 4) A higher CD34+ cell dose may be protective against IFD; 5) Prior IFD did not predict for higher risk of IFD or higher mortality, suggesting these patients should not be excluded from allogeneic HCT. Further studies looking at alternate aGVHD prophylaxis regimens, strategies to increase cell dose infused and better antifungal prophylaxis for these high risk patients are needed to lessen this potentially life threatening complication. Disclosures:Mylonakis:T2 Biosystems: Research Funding; Astellas inc : Research Funding.