Optimizing patient recruitment into clinical trials of antimicrobial-resistant pathogens.

Recruitment of patients with critical priority antimicrobial-resistant (AMR) bacteria into drug approval randomized controlled trials (RCTs) has not been successful to date. Approaching from the viewpoint of clinician-investigators and learning from the experience of AMR-focused investigator-initiated trials, we present suggestions to improve feasibility and efficiency of RCTs evaluating patients with severe infections caused by carbapenem-resistant Gram-negative or other AMR bacteria. Considerations address the trials' eligibility criteria, whether the focus of the trial is pathogen- or syndrome-targeted, trials' case report forms and monitoring, informed consent strategies for the recruitment of extremely ill patients, team dedication and incentives to run the trial and alternative trial designs.

External Validity of a Randomized Controlled Trial on Duration of Antibiotics for the Treatment of Gram-Negative Bacteremia.

Introduction: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial.

Methods: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017.

Wall painting following terminal cleaning with a chlorine solution as part of an intervention to control an outbreak of carbapenem-resistant Acinetobacter baumannii in a neurosurgical intensive care unit in Israel.

Background: To describe the use of wall painting as part of an intervention to control an outbreak of carbapenem-resistant Acinetobacter baumannii (CRAB).

Methods: An interrupted time-series analysis was performed analyzing an intervention in a neurosurgical intensive care unit (NSICU) and an inpatient hematology department in a tertiary level medical center in Israel. The intervention involved wall painting using a water based acrylic paint following patient discharge and terminal cleaning with sodium troclosene as part of an infection control bundle for an outbreak of CRAB in a NSICU and concurrent outbreaks of carbapenem-resistant Enterobacteriaceae (CRE) colonization/infection in the same NSICU and the hematology department.

A systematic review of antimicrobial susceptibility testing as a tool in clinical trials assessing antimicrobials against infections due to gram-negative pathogens.

Background: Antimicrobial susceptibility testing (AST) is the standard of care for treating bacterial infections. In randomized clinical trials of new antimicrobials, AST might not be performed or reported in real time.

Objectives: To determine local, real-time laboratory AST performance, its usage in the trial flow, quality control (QC) of the local testing, central AST performance and the effect of using AST categorization on the trials' primary outcomes.

Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity.

Background: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria.

Utilising sigmoid models to predict the spread of antimicrobial resistance at the country level.

BackgroundThe spread of antimicrobial resistance (AMR) is of worldwide concern. Public health policymakers and pharmaceutical companies pursuing antibiotic development require accurate predictions about the future spread of AMR.AimWe aimed to identify and model temporal and geographical patterns of AMR spread and to predict future trends based on a slow, intermediate or rapid rise in resistance.

Colistin Resistance Development Following Colistin-Meropenem Combination Therapy Versus Colistin Monotherapy in Patients With Infections Caused by Carbapenem-Resistant Organisms.

Background: We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms.

Methods: This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates.

Are all vaccines safe for the pregnant traveller? A systematic review and meta-analysis.

Pregnant travellers and their offspring are vulnerable to severe outcomes following a wide range of infections. Vaccine-preventable diseases can have a particularly severe course in pregnant women, but little is known about the safety of travel vaccines in pregnant women. We performed a systematic review of all published literature concerning the safety of vaccines frequently given to travellers such as yellow fever, MMR (mumps, measles and rubella), influenza, Tdap (tetanus, diphtheria and pertussis), meningococcus, hepatitis A and B, rabies, polio, typhoid fever, tick-borne encephalitis and Japanese encephalitis vaccines.

Antimicrobial use trends, Israel, 2012 to 2017.

BackgroundIn 2012, Israel's National Center for Infection Control initiated a national stewardship programme that included mandatory annual reporting of antimicrobial use. Here we present nationwide Israeli data for the period 2012 to 2017.AimThe goal of this study was to detect trends in antimicrobial use in Israel following the introduction of the stewardship programme, as part of an assessment of the programme's impact.

Antibiotic treatment for invasive nonpregnancy-associated listeriosis and mortality: a retrospective cohort study.

Little evidence exists addressing the clinical value of adding gentamicin to ampicillin for invasive listeriosis. A multicenter retrospective observational study of nonpregnant adult patients with invasive listeriosis (primary bacteremia, central nervous system (CNS) disease, and others) in 11 hospitals in Israel between the years 2008 and 2014 was conducted. We evaluated the effect of penicillin-based monotherapy compared with early combination therapy with gentamicin, defined as treatment started within 48 h of culture results and continued for a minimum of 7 days.

Trends in antimicrobial resistance in Israel, 2014-2017.

We analyzed Israeli national data on antimicrobial susceptibility from bloodstream isolates collected between 2014 and 2017 and compared resistance proportions with those of Europe. The incidence of bloodstream infection (BSI) caused by most antibiotic-resistant organisms remained unchanged or decreased. An exception was increased incidence of BSI caused by third-generation cephalosporin-resistant .

Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial.

Background: Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited.

Methods: This was a randomized, multicenter, open-label, noninferiority trial.

Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial.

Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy.

Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A.

Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial.

Background: Colistin-carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria.

Methods: A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy.

Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer.

Background: The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram-positive infections. Some of these gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment.

Objectives: To assess the effectiveness of empirical anti-gram-positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure.

Predicting Antibiotic Resistance in Urinary Tract Infection Patients with Prior Urine Cultures.

To improve antibiotic prescribing, we sought to establish the probability of a resistant organism in urine culture given a previous resistant culture in a setting endemic for multidrug-resistant (MDR) organisms. We performed a retrospective analysis of inpatients with paired positive urine cultures. We focused on ciprofloxacin-resistant (cipro(r)) Gram-negative bacteria, extended-spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), and carbapenem-resistant nonfermenters (CRNF).

Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol.

Introduction: The emergence of antibiotic-resistant bacteria has driven renewed interest in older antibacterials, including colistin. Previous studies have shown that colistin is less effective and more toxic than modern antibiotics. In vitro synergy studies and clinical observational studies suggest a benefit of combining colistin with a carbapenem.