2 Minute Medicine Rewind November 25, 2019

Long-term impact of an educational antimicrobial stewardship programme in primary care on infections caused by extended-spectrum β-lactamase-producing Escherichia coli in the community: an interrupted time-series analysis.

1. A multi-modal antimicrobial stewardship program in primary care focused on individual educational interviews may improve antibiotic prescription practices and lead to sustained reductions in community-level extended-spectrum B-lactamase-producing Escherichia coli infections.

Evidence Rating Level: 1 (Excellent)

Inappropriate use of antibiotics is a leading cause of antimicrobial resistance. Antimicrobial stewardship programs (ASPs) have been identified as a key aspect of addressing increasing antimicrobial resistance rates. While they have proven utility in the hospital setting, there is little evidence supporting long-term sustainability and effectiveness for these programs in terms of changed prescribing behaviors and decreased resistance rates. Given an increasing proportion of resistant Escherichia coli (E. coli) strains and increasing antibiotic consumption rates, the objective of this quasi-experimental interrupted time series study was to develop a primary care ASP and evaluate its effect on antibiotic use and incidence of resistant E. coli, specifically extended-spectrum B-lactamase-producing (ESBL) strains in urine samples, across Spanish patient populations. Involving multidisciplinary teams of general practitioners, pediatricians, primary care pharmacists and epidemiologists across 214 primary health centers of four Spanish primary health care districts, the program used a combination of web-based material, training courses, seminars and face-to-face sessions. Five educational interventions were implemented: regional and local level educational and program dissemination; open online health courses regarding appropriate antimicrobial practices for local teams; regular clinical sessions to update local protocols for management of common infections; educational interviews with one-to-one interventions; and development of quarterly reports for all participating centres with analytical data for their outcomes, for feedback and benchmarking. The primary outcome was inappropriate antibiotic prescribing through educational one-to-one interviews, deemed as such when one or more of the items of the questionnaire administered during these sessions was answered negatively. Enrolling 1,387 physicians serving a mean population of 1,937,512 adults and children between January 2012 and December 2017, 24,150 educational interviews were conducted as part of the program. Overall, 1,794/4,917 (36.5%) of antibiotic prescriptions were deemed inappropriate in 2014, compared to 1,793/6,6665 (26.9%) in 2017 (p<0.0001). A sustained reduction in use of ciprofloxacin (relative effect -15.9%, 95% CI -23.9 to -8.0) and cephalosporins (-22.6%, 95% CI -35.9 to -9.2) were seen, with an associated sustained increase in amoxicillin use (22.2%, 95% CI 6.4 to 38.0) and fosfomycin (6.1%, 95% CI 2.6 to 9.6%). ESBL E. coli incidence density decreased significantly after the program’s initiation (relative reduction, -65.6%, 95% CI -68.2 to -63.0). Study findings suggest that such ASP programs that employ a peer-to-peer educational interview component may improve antimicrobial use rates and reduce bacterial resistance in community settings, with sustainable clinical benefits over time in terms of resistance rates and prescribing patterns. The implementation of such programs in primary care remains encouraged, with further studies warranted to definitively confirm the value of the individual face-to-face educational interviews.

Safety and immunogenicity of the oral, inactivated, enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi children and infants: a double-blind, randomised, placebo-controlled phase 1/2 trial

1. Enterotoxigenic Escherichia coli vaccination may provide significant immunogenic benefits in young children and infants in low- and middle-income countries with minimal associated toxicity.

Evidence Rating Level: 1 (Excellent)

Enterotoxigenic Escherichia coli (E. coli) is associated with diarrhea, stunting and significant morbidity and mortality in children, particularly from low-income and middle-income countries. A University of Gothenburg team has developed an enterotoxigenic E. coli vaccine (ETVAX) with strains of recombinant E. coli overexpressing the most prevalent colonization factors at higher concentrations. ETVAX was proven to be safe, provided significant fecal secretory IgA, and IgA antibody lymphocyte secretory responses across all colonization factors, along with immunologic memory when tested in Swedish adults. Its immunogenicity and safety were also proven in Bangladeshi adults. This large-scale, dose-escalation, age-descending phase 1/2 Bangladesh-based trial aimed to evaluate the safety and immunogenicity of ETVAX in children, with the primary objective of establishing the largest tolerated dose of ETVAX and the potential of the vaccine to induce mucosal and systemic immune responses against five primary antigens. Healthy children aged 6 to 59 months were deemed eligible and were randomly assigned using block randomization to receive ETVAX with or without a double-mutant heat-labile enterotoxin, or placebo. Two doses were administered two weeks apart across arms. The primary endpoint was safety and tolerability in children receiving at least one vaccine dose, with antibody response to vaccine antigens, defined as a minimum of a two-fold increase in antibody levels from baseline, was evaluated as a secondary endpoint. Overall, 430 children were enrolled and randomly assigned between December 2015 and January 2017, and all participants received at least one vaccine dose. The most common adverse event reported was emesis (52/430 participants; 12.1%). Only three serious adverse events occurred and were considered unrelated to the intervention. Most adverse events were reported as mild. While antibody responses were less frequent and of lower magnitude among younger children aged 6 to 11 months, most participants aged 12 to 23 months and 24 to 59 months had detectable IgA antibody responses against all five primary vaccine antigens. Fifty-six percent of infants aged 6 to 11 months who received treatment developed mucosal responses to at least three vaccine antigens, compared to 29% of infants receiving placebo. Study findings suggest that infants and children may develop significant immune responses with administration of ETVAX with minimal serious toxicity, which may further be enhanced by co-administration of a double-mutant heat-labile enterotoxin.

Global and regional estimates of the contribution of herpes simplex virus type 2 infection to HIV incidence: a population attributable fraction analysis using published epidemiological data

1. Herpes simplex virus type 2 (HSV-2) infections significantly contribute to the global burden of sexually-acquired HIV infections.

Evidence Rating Level: 2 (Good)

There is a known strong biological association between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus (HIV) acquisition, transmissibility, and disease severity. This analysis provides the first global and regional-level analysis of population attributable fractions (PAFs) and incidence of HIV infections attributable to HSV-2 infection, with subgroup analyses for female sex workers (FSWs) and men who have sex with men (MSM). Classic epidemiological statistics of polytomous exposure to estimate global and regional PAF and incident HIV infections by age, sex and timing, with pooled adjusted relative risk estimates from systematic review data were used to analyze the association of HSV-2 infection on HIV acquisition. Analyses revealed that 420,000 (95% CI 317,000 to 546,000; PAF 29.6% [95% CI 22.9 to 37.1]) of 1.4 million sexually-acquired adult HIV infections in 2016 were attributable to HSV-2 infections. The largest contribution of HSV-2 infections was evident in the African region, among women, those aged 25 to 49 years, and those with established HSV-2 infections. Study findings suggest a significant burden of underlying HSV-2 infections in sexually-transmitted HIV acquisition, with the greatest burden of HSV-2 infections in areas where the infection is most prevalent.

Rectal indomethacin dose escalation for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography in high-risk patients: a double-blind, randomised controlled trial

1. Dose escalation of rectal indomethacin does not provide any benefit in preventing pancreatitis in high-risk patients post-endoscopic retrograde cholangiopancreatography.

Evidence Rating Level: 1 (Excellent)

Pancreatitis is the most frequent and concerning complication of endoscopic retrograde cholangiopancreatography (ERCP). Use of rectal non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and diclofenac peri-procedurally has been shown to produce a reduction in pancreatitis in high-risk patients, and has been adopted into practice. Despite the introduction of prophylactic pharmacotherapy or stent placement, the incidence of pancreatitis in this population remains approximately 10%. The objective of this randomized, double-blind superiority trial was to examine whether a dose escalation strategy with a higher initial dose followed by a second dose of NSAID would be superior relative to standard NSAID dosing for prevention of pancreatitis post-ERCP in high-risk patients. One thousand thirty-seven patients deemed to be at high risk for pancreatitis post-ERCP were enrolled between July 2013 and March 2018 from six American tertiary medical centers. They were randomized post-operatively to either two 50mg indomethacin suppositories and a placebo suppository (standard dose group) or three 50mg indomethacin suppositories with an additional 50mg suppository four hours postoperatively (high-dose group). The primary outcome was pancreatitis post-ERCP. A total of 141 (14%) of 1,037 patients in the trial developed pancreatitis post-operatively. Pancreatitis occurred in 76 (15%) of 515 participants in the standard dose group and 65 (12%) of 522 patients in the high-dose group (RR 1.19, 95% CI 0.87 to 1.61, p = 0.32). Nineteen study drug-related adverse events were reported, with clinically significant bleeding (n=14) being most common, and having comparable incidences between groups (1% vs. 1% in standard dose and high-dose groups). Other adverse events included acute kidney injury (0% vs. 1%), non-ST elevation myocardial infarction (<1% vs. 0%) and transient ischemic attack (<1% vs. 0%). Study findings therefore suggest no significant benefit with dose escalation of rectal indomethacin for pancreatitis prophylaxis in high-risk patients post-ERCP and do not warrant a change in current clinical practice.

Survival outcomes after laparoscopy-assisted distal gastrectomy versus open distal gastrectomy with nodal dissection for clinical stage IA or IB gastric cancer (JCOG0912): a multicentre, non-inferiority, phase 3 randomised controlled trial.

1. Laparoscopic-assisted distal gastrectomy is non-inferior to open distal gastrectomy for clinical stage IA and IB gastric cancer in terms of relapse-free survival.

Evidence Rating Level: 1 (Excellent)

Laparoscopy-assisted distal gastrectomy (LADG) is now increasingly used for early stage gastric cancer, with evidence showing reduced intraoperative blood loss, lower postoperative pain, and faster recovery than open distal gastrectomy (ODG). While retrospective studies have shown equivalent survival between the two operations, LADG is technically complex and non-randomized comparative studies may be affected by selection bias in terms of operator surgical skill level. This open-label, multi-center, non-inferiority phase III randomized controlled trial aimed to compare LADG to ODG with regards to long-term relapse-free survival. Nine hundred twenty-one non-obese highly-functional (Eastern Cooperative Oncology Group [ECOG] performance status 0 or 1) adults with histologically confirmed early-stage (clinical stage I) gastric adenocarcinoma in the middle or lower third of the stomach that was amenable to curative resection were enrolled between March 2010 and November 2013. Participants were randomized to ODG(n=459) or LADG (n=462). The non-inferiority margin was established at a hazard ratio of 1.54. Of those randomized, 912 (99%) of participants had their assigned surgery. As per intention-to-treat analyses, five-year relapse-free rates were comparable between groups (94.0% [95% CI 91.4 to 95.9] vs. 95.1% [92.7 to 96.8]. Relapse free survival was similar between groups (HR 0.84, 90% CI 0.56 to 1.27). Rates of bowel obstruction, the most common serious adverse event, were similar between groups as well (2% vs. 1%). Study findings suggest that LADG is non-inferior to ODG in terms of relapse-free survival, and support LADG as standard of care over open surgery for stage I gastric cancer, alongside previous evidence supporting the efficacy and safety of laparoscopic-assisted total and partial gastrectomies in related contexts.

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