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Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration.

BackgroundDesirability of outcome ranking (DOOR) is an innovative approach in clinical trials to evaluate the global benefits and risks of an intervention. We developed and validated a DOOR endpoint for Staphylococcus aureus bloodstream infection (BSI) through a survey to infectious diseases clinicians and secondary analysis of trial data.MethodsWe administered a survey of 20 cases of S. aureus BSI, asking respondents to rank outcomes by global desirability. Correlations and percentage of pairwise agreement among rankings were estimated to inform development of a DOOR endpoint, which was applied to 2 prior S. aureus BSI trials. The probability that a patient randomly assigned to experimental treatment would have a better DOOR ranking than if assigned to control was estimated. Results were also analyzed using partial credit, which is analogous to scoring an academic test, assigning 100% to the most desirable outcome, 0% to the least, and "partial credit" to intermediate ranks.ResultsForty-two recipients (97%) completed the survey. The DOOR endpoint fitting these rankings (r = 0.89; 95% confidence interval, 0.67 to 0.94) incorporated survival plus cumulative occurrence of adverse events, cure, infectious complications, and ongoing symptoms. Tailored versions of this endpoint were applied to 2 S. aureus BSI trials, and both demonstrated no benefit of the experimental treatment using DOOR and partial credit analysis.ConclusionsUsing S. aureus BSI as an exemplar, we developed a DOOR endpoint that can be used as a template for development of DOOR endpoints for other diseases. Future trials can incorporate DOOR to allow for global assessment of patient experience.

Objectives: Fever following transcatheter aortic valve implantation (TAVI) is a common phenomenon, attributed mostly to inflammatory response which may impact outcome. Systemic inflammatory response may be triggered by multiple factors, most associated with the TAVI procedure itself. However, there are no data regarding the incidence of fever following TAVI in contemporary era with newer generation devices. Our primary objective was to measure temporal trends in fever incidence and features following TAVI. Methods: We analyzed a retrospective cohort of 802 consecutive patients who underwent TAVI at our institution between November 2008 and February 2018. We identified and characterized all patients who developed fever (>38.0°C from any cause) within the first 72 h following the procedure and analyzed incidence and characteristics stratified into 3 time frames: 2008–2014, 2014–2016, and 2016–2018. Results: Following TAVI, 190 (23.7%) patients developed fever (mean age 82.3 ± 5.2 years, 64.2% female). An infectious etiology was evident in only 32.1% of cases. The frequency decreased gradually and significantly across timeframes (32.8, 23.6, and 14.5%, respectively, p < 0.001). In a multivariate regression analysis, 1st generation CoreValve (HR 1.91; CI 95% 1.2–3.04, p = 0.006) was found to be associated with higher incidence of fever in addition to female gender, vascular complications, transfemoral access, and reduced GFR. Conclusions: Fever incidence post TAVI decreased significantly throughout the last decade. The higher rate of fever in the early years of TAVI was likely associated with first-generation devices, vascular complications, and reduced GFR. [ABSTRACT FROM AUTHOR]

Background little is known on the clinical implications of vancomycin trough levels among older patients. Objective to evaluate the association between vancomycin levels and outcomes among older versus younger patients. Design retrospective study. Subjects patients aged 18–64 and ≥65 years treated with vancomycin for documented methicillin resistant Staphylococcus aureus (MRSA) infections. Methods we compared the effectiveness and toxicity of vancomycin according to trough levels in older versus younger patients. Subgroup analysis of patients with glomerular filtration rate (GFR) > 60 ml/min/1.73 m2 was performed. Results we included 181 patients aged ≥65 years and 104 younger patients. Mean age in the older group was 76.9 ± 8 years versus 50.9 ± 12.4 in the younger group. Vancomycin trough levels and 24-hours area under the curve to minimal inhibitory concentrations (AUC/MIC) were significantly higher in older patients who were also significantly more likely to achieve trough levels of ≥15 mg/l within 4 days, (98/181 (54.1%) vs. 38/104 (36.5%) in younger patients, P  = 0.004). Results were similar among patients with GFR > 60. Thirty-day mortality was significantly higher in older (74/181, 40.9% vs. 13/104, 12.5%, respectively, P  < 0.001). There was no association between vancomycin trough levels and mortality among older patients. No significant differences were demonstrated in clinical or microbiological success or nephrotoxicity. Conclusions applying uniform dosing recommendations across age groups among adults with MRSA infections results in higher vancomycin levels and AUC/MIC in older versus younger patients. Yet, mortality rates remain higher among older adults. Prospective studies are needed to define the optimal approach for using this drug in older patients. [ABSTRACT FROM AUTHOR]

Background: Ceftazidime/avibactam is approved for complicated intra-abdominal and urinary tract infections (UTIs) based on results from randomized controlled trials (RCTs). Data regarding its effectiveness in treating hospital-acquired infections or resistant pathogens have not been systematically compiled.Methods: A systematic review and meta-analysis including RCTs evaluating ceftazidime/avibactam versus comparator for the treatment of any infection. Primary outcome was 30 day all-cause mortality. Subgroups of hospital-acquired infections and specific resistance phenotypes were planned.Results: Seven publications (eight trials, 4093 patients) were included, reporting a baseline ∼25% of ESBL-carrying Enterobacteriaceae. No significant difference between ceftazidime/avibactam and comparator (mostly carbapenem) was demonstrated for 30 day all-cause mortality, late follow-up mortality and clinical response [relative risk (RR) 1.10, 95% CI 0.70-1.72, P = 0.69; RR 1.23, 95% CI 0.87-1.76, P = 0.25; RR 0.98, 95% CI 0.96-1.01, P = 0.21, respectively, without significant heterogeneity]. Higher microbiological response rate was demonstrated with ceftazidime/avibactam in patients with UTI (RR 1.14, 1.0-1.29, P = 0.05, I2 = 51%). No significant difference in clinical response was demonstrated for patients with ceftazidime-resistant pathogens (RR 1.02, 95% CI 0.94-1.10, P = 0.66, I2 = 0%). Results for other subgroups of resistant pathogens or hospital-acquired infection were not available. Serious adverse events (SAEs) were significantly more common with ceftazidime/avibactam (RR 1.24, 95% CI 1.00-1.54, P = 0.05, I2 = 0%).Conclusions: Ceftazidime/avibactam is clinically and microbiologically as effective as carbapenems for treatment of infections in a setting of ∼25% ESBL-carrying Enterobacteriaceae. Safety of the drug should be further evaluated owing to a higher rate of SAEs compared with carbapenems. Further studies should assess the drug's effectiveness in the treatment of carbapenemase-producing Enterobacteriaceae. [ABSTRACT FROM AUTHOR]

Background Tigecycline is a novel glycylcycline that exhibits broad-spectrum antibacterial activity. Recently, the US FDA issued a warning concerning increased mortality with tigecycline in randomized controlled trials (RCTs). Methods We conducted a systematic review and meta-analysis of RCTs that compared tigecycline with any other antibiotic regimen for the treatment of any infection. A comprehensive search, without publication status or other restrictions, was conducted. The primary outcome was overall 30 day mortality. The secondary outcome included clinical and microbiological failure, superinfections and adverse events (AEs). The trials’ risks of bias and their effects on results were assessed. Two reviewers independently extracted the data. Individual trials’ relative risks (RRs) were pooled using a fixed effect meta-analysis. Results Fifteen trials (7654 patients) were included. Overall mortality was higher with tigecycline compared with other regimens [RR 1.29, 95% confidence interval (CI) 1.02–1.64, without heterogeneity]. The type of infection assessed and the trials’ reported risks of bias did not affect this result. Clinical failure was significantly higher with tigecycline (RR 1.16, 95% CI 1.06–1.27) and non-statistically significant higher rates of microbiological failure were demonstrated (RR 1.13, 95% CI 0.99–1.30). Development of septic shock was significantly more frequent with tigecycline (RR 7.01, 95% CI 1.27–38.66). Superinfections were significantly more common with tigecycline and so were AEs, including all AEs and AEs requiring discontinuation. Conclusions In the light of the increased mortality, probably explained by decreased clinical and microbiological efficacy, clinicians should avoid tigecycline monotherapy in the treatment of severe infections and reserve it as a last-resort drug. [ABSTRACT FROM PUBLISHER]

Systematic reviews and meta-analyses have made a major contribution to the evidence-based management of infections in cancer patients. We review the contribution of systematic reviews with regard to antibiotic, antifungal, antiviral and Pneumocystis pneumonia prophylaxis; antibiotic and antifungal treatment of febrile neutropenia; use of intravenous immunoglobulins, and infection control strategies during neutropenia. We focus on limitations of randomized controlled trials and the way systematic reviews have addressed and resolved some of these limitations. Systematic reviews allow us to ask the right clinical question; consider the most relevant clinical outcome; address the problem of small trials and rare outcomes; address external validity and bias in randomized controlled trials, and point at gaps in evidence. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Immunosuppression reduction is a common practice in the management of bacterial infection among kidney transplant recipients (KTRs). This practice, however, is based on limited evidence. Methods: Retrospective study comparing clinical outcomes of KTRs whose antimetabolite was discontinued vs continued during hospitalization due to bacterial infection, considering calcineurin inhibitors (CNI) levels. Primary outcome was a composite of clinical failure at day 5; all‐cause mortality; and/or re‐hospitalization at 90 days. Multivariable analysis of risk factors for the primary outcome was performed using a propensity‐matched cohort. Results: We included 183 KTRs hospitalized with bacterial infection. Neither discontinuation of antimetabolites nor lower levels of CNI at infection onset were associated with a significant decrease the composite primary outcome. No significant difference in graft loss or rejection was demonstrated between patients with low vs high CNI levels or discontinuation vs continuation of antimetabolite. In multivariable analysis, CNI levels and management of antimetabolite were not significantly associated with adverse outcome. Conclusions: Immunosuppression reduction in hospitalized KTRs with bacterial infection did not offer a clinical advantage in terms of mortality, re‐hospitalization, or clinical success. An interventional study evaluating continuation of immunosuppression vs reduction should be considered. [ABSTRACT FROM AUTHOR]

Background: There is no consensus on the optimal management of immunosuppression during bacterial infections among solid organ transplant recipients. Methods: A multicenter, cross‐sectional survey, of high‐volume kidney and liver transplant centers across US and Europe. Structured questionnaires including six multiple‐choice questions concerning the management of immunosuppression during infection were distributed among 381 centers. Results: A total of 124 (33%) centers fully completed the questionnaire: 67 liver, 57 kidney centers. Participating centers reported heterogenous approaches to immunosuppression management for all types of immunosuppressive drugs. Notably, kidney centers reported similar frequencies of either discontinuation (19%), continuation (19%), or dose reduction (17.5%) of antimetabolites; discontinuation only for life‐threatening infection (17.5%) or case by case decisions (27%). Calcineurin inhibitors (CNI) management was heterogenous mostly among liver centers, with 8% discontinuing the CNI, 18% continuing, and 22% reducing dose. Heterogenous approaches to management of steroids and inhibitors of the mammalian target of rapamycin were also demonstrated. Conclusions: Immunosuppression management during bacterial infection is heterogenous in US and European centers. Immunosupression reduction (ISR) during infection is a common practice, though supported by limited evidence. Demonstrating high heterogeneity in the approach to ISR, together with the equivocal results of clinical studies, support consideration of an interventional clinical trial. [ABSTRACT FROM AUTHOR]