Editorial: Teaching Professionalism in Surgery and Beyond

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IGNITE4 : Results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections

Funding Information: Financial support. This work was supported by Tetraphase Pharmaceuticals Inc. Funding Information: Potential conflicts of interest. J. S. S. has received support from Tetraphase Pharmaceuticals Inc. during the production of this manuscript and has served as a consultant to Merck, Pfizer, GlaxoSmithKline, and Melinta outside of the submitted work. A. S received support from Tetraphase Pharmaceuticals Inc. during the production of this manuscript. J. G. received research funding from Tetraphase Pharmaceuticals Inc. for his role as principal investigator of this study. K. L. and L. T. are employed by Tetraphase Pharmaceuticals Inc. D. E. reports grants from Tetraphase Pharmaceuticals Inc. during the conduct of the study and grants from Merck outside of the submitted work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Publisher Copyright: © 2018 The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.Background: Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multidrug-resistant bacteria including extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae. Methods: IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacycline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated. Results: Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively. Conclusions: Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens. Clinical Trials Registration: NCT01844856.publishersversionPeer reviewe

Effectiveness of 80% vs 30–35% fraction of inspired oxygen in patients undergoing surgery: an updated systematic review and meta-analysis

Background In 2016, the World Health Organization (WHO) strongly recommended the use of a high fraction of inspired oxygen (FiO2) in adult patients undergoing general anaesthesia to reduce the risk of surgical site infection (SSI). Since then, further trials have been published, trials included previously have come under scrutiny, and one article was retracted. We updated the systematic review on which the recommendation was based. Methods We performed a systematic literature search from January 1990 to April 2018 for RCTs comparing the effect of high (80%) vs standard (30–35%) FiO2 on the incidence of SSI. Studies retracted or under investigation were excluded. A random effects model was used for meta-analyses; the sources of heterogeneity were explored using meta-regression. Results Of 21 RCTs included, six were newly identified since the publication of the WHO guideline review; 17 could be included in the final analyses. Overall, no evidence for a reduction of SSI after the use of high FiO2 was found [relative risk (RR): 0.89; 95% confidence interval (CI): 0.73–1.07]. There was evidence that high FiO2 was beneficial in intubated patients [RR: 0.80 (95% CI: 0.64–0.99)], but not in non-intubated patients [RR: 1.20 (95% CI: 0.91–1.58); test of interaction; P=0.048]. Conclusions The WHO updated analyses did not show definite beneficial effect of the use of high perioperative FiO2, overall, but there was evidence of effect of reducing the SSI risk in surgical patients under general anaesthesia with tracheal intubation. However, the evidence for this beneficial effect has become weaker and the strength of the recommendation needs to be reconsidered

Ertapenem versus piperacillin/tazobactam for the treatment of complicated infections: a meta-analysis of randomized controlled trials

<p>Abstract</p> <p>Background</p> <p>Ertapenem, a new carbapenem with a favorable pharmacokinetic profile, has been approved for the treatment of complicated intra-abdominal Infections (cIAIs), acute pelvic infections (APIs) and complicated skin and skin-structure infections (cSSSIs). The aim of this study is to compare the efficacy and safety of ertapenem with piperacillin/tazobactam, which has been reported to possess good efficacy for the treatment of these complicated infections.</p> <p>Methods</p> <p>We performed a meta-analysis of randomized controlled trials identified in PubMed, Cochrane library and Embase that compared the efficacy and safety of ertapenem with piperacillin/tazobactam for the treatment of complicated infections including cIAIs, APIs, cSSSIs. The primary efficacy outcome was clinical treatment success assessed at the test-of-cure visit. The primary safety outcome was drug related clinical and laboratory adverse events occurred during the treatment and the post-treatment period.</p> <p>Result</p> <p>Six RCTs, involving 3161 patients, were included in our meta-analysis. Ertapenem was associated similar clinical treatment success with piperacillin/tazobactam for complicated infections treatment (clinically evaluable population, 1937 patients, odds ratios: 1.15, 95% confidence intervals: 0.89-1.49; modified intention to treat population, 2855 patients, odds ratios: 1.03, 95% confidence intervals: 0.87-1.22). All of secondary efficacy outcomes analysis obtained similar findings with clinical treatment success. No difference was found about the incidence of drug related adverse events between ertapenem and piperacillin/tazobactam groups.</p> <p>Conclusion</p> <p>This meta-analysis provides evidence that ertapenem 1 g once a day can be used as effectively and safely as recommended dose of piperacillin/tazobactam, for the treatment of complicated infections, particularly of mild to moderate severity. It is an appealing option for the treatment of these complicated infections.</p

Efficacy and safety of moxifloxacin in hospitalized patients with secondary peritonitis : pooled analysis of four randomized phase III trials

Background: Secondary peritonitis is an advanced form of complicated intra-abdominal infection (cIAI) requiring hospitalization, surgical source control, and empiric antibiotic therapy against causative aerobic and anaerobic bacteria. Methods: This pooled analysis of four prospective, active-controlled randomized clinical trials compared the efficacy and safety of moxifloxacin with that of comparator antibiotics in patients with confirmed secondary peritonitis. The primary efficacy endpoint was clinical success rate at test-of-cure (TOC) between day 10 and 45 post-therapy in the per-protocol (PP) population. Safety and clinical efficacy were assessed also in the intent-to-treat population (ITT). Bacteriological success was assessed at TOC in the microbiologically-valid population as a secondary efficacy endpoint. Results: Overall clinical success rates at TOC were 85.3% (431 of 505 patients) in the moxifloxacin and 88.4% (459 of 519 patients) in the comparator treatment groups (PP population, point estimate for the difference in success rates: -3.0%; 95% CI -7.06%, 1.05%), respectively. Similar clinical success rates between moxifloxacin and comparators were observed by anatomical site of infection, and ranged from 80.6% to 100% for moxifloxacin and from 71.4% to 96.6% for comparators, respectively. Bacteriologic success rates were similar with moxifloxacin (82.4%) and comparators (86.8%), respectively. The proportion of patients experiencing any treatment-emergent adverse events was slightly higher with moxifloxacin (67.3%) versus comparators (59.8%). Rates of drug-related adverse events (20.9% versus 20.0%) and deaths (4.3% versus 3.4%) were similar in moxifloxacin and comparator groups; none of the deaths were drug-related. Conclusions: The data suggests that once-daily IV (or IV/PO) moxifloxacin has a comparable efficacy and safety profile to antibiotic regimens approved previously in the subgroup of patients with secondary peritonitis of mild-to-moderate severity

Safety of 80% vs 30–35% fraction of inspired oxygen in patients undergoing surgery: a systematic review and meta-analysis

Background: Evidence-based guidelines from the World Health Organization (WHO) have recommended a high (80%) fraction of inspired oxygen (FiO2) to reduce surgical site infection in adult surgical patients undergoing general anaesthesia with tracheal intubation. However, there is ongoing debate over the safety of high FiO2. We performed a systematic review to define the relative risk of clinically relevant adverse events (AE) associated with high FiO2. Methods: We reviewed potentially relevant articles from the WHO review supporting the recommendation, including an updated (July 2018) search of EMBASE and PubMed for randomised and non-randomised controlled studies reporting AE in surgical patients receiving 80% FiO2 compared with 30–35% FiO2. We assessed study quality and performed meta-analyses of risk ratios (RR) comparing 80% FiO2 against 30–35% for major complications, mortality, and intensive care admission. Results: We included 17 moderate–good quality trials and two non-randomised studies with serious-critical risk of bias. No evidence of harm with high FiO2 was found for major AE in the meta-analysis of randomised trials: atelectasis RR 0.91 [95% confidence interval (CI) 0.59–1.42); cardiovascular events RR 0.90 (95% CI 0.32–2.54); intensive care admission RR 0.93 (95% CI 0.7–1.12); and death during the trial RR 0.49 (95% CI 0.17–1.37). One non-randomised study reported that high FiO2 was associated with major respiratory AE [RR 1.99 (95% CI 1.72–2.31)]. Conclusions: No definite signal of harm with 80% FiO2 in adult surgical patients undergoing general anaesthesia was demonstrated and there is little evidence on safety-related issues to discourage its use in this population