Single-drug versus combination antimicrobial therapy in critically ill patients with hospital-acquired pneumonia and ventilator-associated pneumonia due to Gram-negative pathogens: a multicenter retrospective cohort study.

KEY MESSAGES: In this study including 391 critically ill patients with nosocomial pneumonia due to Gram-negative pathogens, combination therapy was not associated with a reduced hazard of death at Day 28 or a greater likelihood of clinical cure at Day 14. No over-risk of AKI was observed in patients receiving combination therapy. BACKGROUND: The benefits and harms of combination antimicrobial therapy remain controversial in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP) or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria. METHODS: We included all patients in the prospective multicenter OutcomeRea database with a first HAP, vHAP or VAP due to a single Gram-negative bacterium and treated with initial adequate single-drug or combination therapy. The primary endpoint was Day-28 all-cause mortality. Secondary endpoints were clinical cure rate at Day 14 and a composite outcome of death or treatment-emergent acute kidney injury (AKI) at Day 7. The average effects of combination therapy on the study endpoints were investigated through inverse probability of treatment-weighted regression and multivariable regression models. Subgroups analyses were performed according to the resistance phenotype of the causative pathogens (multidrug-resistant or not), the pivotal (carbapenems or others) and companion (aminoglycosides/polymyxins or others) drug classes, the duration of combination therapy (< 3 or ≥ 3 days), the SOFA score value at pneumonia onset (< 7 or ≥ 7 points), and in patients with pneumonia due to non-fermenting Gram-negative bacteria, pneumonia-related bloodstream infection, or septic shock. RESULTS: Among the 391 included patients, 151 (38.6%) received single-drug therapy and 240 (61.4%) received combination therapy. VAP (overall, 67.3%), vHAP (16.4%) and HAP (16.4%) were equally distributed in the two groups. All-cause mortality rates at Day 28 (overall, 31.2%), clinical cure rate at Day 14 (43.7%) and the rate of death or AKI at Day 7 (41.2%) did not significantly differ between the groups. In inverse probability of treatment-weighted analyses, combination therapy was not independently associated with the likelihood of all-cause death at Day 28 (adjusted odd ratio [aOR], 1.14; 95% confidence interval [CI] 0.73-1.77; P = 0.56), clinical cure at Day 14 (aOR, 0.79; 95% CI 0.53-1.20; P = 0.27) or death or AKI at Day 7 (aOR, 1.07; 95% CI 0.71-1.63; P = 0.73). Multivariable regression models and subgroup analyses provided similar results. CONCLUSIONS: Initial combination therapy exerts no independent impact on Day-28 mortality, clinical cure rate at Day 14, and the hazard of death or AKI at Day 7 in critically ill patients with mono-bacterial HAP, vHAP or VAP due to Gram-negative bacteria.

Measuring Basic Reproduction Number to Assess Effects of Nonpharmaceutical Interventions on Nosocomial SARS-CoV-2 Transmission.

Outbreaks of SARS-CoV-2 infection frequently occur in hospitals. Preventing nosocomial infection requires insight into hospital transmission. However, estimates of the basic reproduction number (R0) in care facilities are lacking. Analyzing a closely monitored SARS-CoV-2 outbreak in a hospital in early 2020, we estimated the patient-to-patient transmission rate and R0. We developed a model for SARS-CoV-2 nosocomial transmission that accounts for stochastic effects and undetected infections and fit it to patient test results. The model formalizes changes in testing capacity over time, and accounts for evolving PCR sensitivity at different stages of infection. R0 estimates varied considerably across wards, ranging from 3 to 15 in different wards. During the outbreak, the hospital introduced a contact precautions policy. Our results strongly support a reduction in the hospital-level R0 after this policy was implemented, from 8.7 to 1.3, corresponding to a policy efficacy of 85% and demonstrating the effectiveness of nonpharmaceutical interventions.

Risk stratification for selecting empiric antibiotherapy during and after COVID-19.

PURPOSE OF REVIEW: SARS-CoV-2 deeply modified the risk of bacterial infection, bacterial resistance, and antibiotic strategies. This review summarized what we have learned. RECENT FINDINGS: During the COVID-19 pandemic, we observed an increase in healthcare-acquired infection and multidrug-resistant organism-related infection, triggered by several factors: structural factors, such as increased workload and ongoing outbreaks, underlying illnesses, invasive procedures, and treatment-induced immunosuppression. The two most frequently healthcare-acquired infections described in patients hospitalized with COVID-19 were bloodstream infection, related or not to catheters, health-acquired pneumonia (in ventilated or nonventilated patients). The most frequent species involved in bacteremia were Gram-positive cocci and Gram-negative bacilli in health-acquired pneumonia. The rate of Gram-negative bacilli is particularly high in late-onset ventilator-associated pneumonia, and the specific risk of Pseudomonas aeruginosa- related pneumonia increased when the duration of ventilation was longer than 7 days. A specificity that remains unexplained so far is the increase in enterococci bacteremia. SUMMARY: The choice of empiric antibiotimicrobials depends on several factors such as the site of the infection, time of onset and previous length of stay, previous antibiotic therapy, and known multidrug-resistant organism colonization. Pharmacokinetics of antimicrobials could be markedly altered during SARS-CoV-2 acute respiratory failure, which should encourage to perform therapeutic drug monitoring.

Faecal carriage of multidrug-resistant bacteria and associated risk factors: results from a point prevalence study.

OBJECTIVES: Since 2003, incidences of carbapenemase-producing Gram-negative bacilli (CP-GNB) and vancomycin-resistant Enterococcus faecium (VRE) have steadily increased in France. We therefore conducted a point prevalence study to estimate carriage rates of CP-GNB, VRE and ESBL-producing Enterobacterales (ESBL-PE) and associated risk factors. METHODS: Between September 2019 and January 2020, all inpatients hospitalized on a given day in 11 teaching hospitals in the Paris urban area were eligible. Patient interviews and rectal swab screening results were recorded by dedicated nurses. The swabs were plated onto selective chromogenic media and processed using the GeneXpert® system. RESULTS: Of 2396 patients, 364 (15.2%) yielded at least one multiresistant bacterial isolate, including 29 CP-GNB carriers (1.2%), 13 VRE carriers (0.5%) and 338 ESBL-PE carriers (14%). In 15 patients (4.4% of ESBL-PE carriers and 36.6% of CP-GNB/VRE carriers), concomitant CP-GNB/VRE and ESBL-PE carriage was observed. In 7/29 CP-GNB and 7/13 VRE carriers, carbapenemase production and vanA in the screening samples was only detected with Xpert® tests. The OXA-48 gene was predominant in 13/34 CP-GNB isolates from 29 carriers. From the 338 ESBL-PE carriers, 372 isolates were recovered, mainly Escherichia coli (61.2%). Among 379 children, 1.1% carried a CP-GNB/VRE strain, and 12.4% carried an ESBL strain. Previous hospitalization outside mainland France, previous antimicrobial treatment and previous ESBL-PE carriage were the main risk factors associated with CP-GNB and/or VRE carriage. CONCLUSIONS: The low CP-GNB and VRE prevalence likely reflects the French policy to limit intrahospital spread of CP-GNB and VRE strains.

A Conceptual Discussion About the Basic Reproduction Number of Severe Acute Respiratory Syndrome Coronavirus 2 in Healthcare Settings.

To date, no specific estimate of R0 for SARS-CoV-2 is available for healthcare settings. Using interindividual contact data, we highlight that R0 estimates from the community cannot translate directly to healthcare settings, with pre-pandemic R0 values ranging 1.3-7.7 in 3 illustrative healthcare institutions. This has implications for nosocomial COVID-19 control.

An International Prospective Cohort Study To Validate 2 Prediction Rules for Infections Caused by Third-generation Cephalosporin-resistant Enterobacterales.

BACKGROUND: The possibility of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacterales (3GC-R-BSI) leads to a trade-off between empiric inappropriate treatment (IAT) and unnecessary carbapenem use (UCU). Accurately predicting 3GC-R-BSI could reduce IAT and UCU. We externally validate 2 previously derived prediction rules for community-onset (CO) and hospital-onset (HO) suspected bloodstream infections. METHODS: In 33 hospitals in 13 countries we prospectively enrolled 200 patients per hospital in whom blood cultures were obtained and intravenous antibiotics with coverage for Enterobacterales were empirically started. Cases were defined as 3GC-R-BSI or 3GC-R gram-negative infection (3GC-R-GNI) (analysis 2); all other outcomes served as a comparator. Model discrimination and calibration were assessed. Impact on carbapenem use was assessed at several cutoff points. RESULTS: 4650 CO infection episodes were included and the prevalence of 3GC-R-BSI was 2.1% (n = 97). IAT occurred in 69 of 97 (71.1%) 3GC-R-BSI and UCU in 398 of 4553 non-3GC-R-BSI patients (8.7%). Model calibration was good, and the AUC was .79 (95% CI, .75-.83) for 3GC-R-BSI. The prediction rule potentially reduced IAT to 62% (60/97) while keeping UCU comparable at 8.4% or could reduce UCU to 6.3% (287/4553) while keeping IAT equal. IAT and UCU in all 3GC-R-GNIs (analysis 2) improved at similar percentages. 1683 HO infection episodes were included and the prevalence of 3GC-R-BSI was 4.9% (n = 83). Here model calibration was insufficient. CONCLUSIONS: A prediction rule for CO 3GC-R infection was validated in an international cohort and could improve empirical antibiotic use. Validation of the HO rule yielded suboptimal performance.

Stewardship program on carbapenem prescriptions in a tertiary hospital for adults and children in France: a cohort study.

Antimicrobial stewardship programs aim at reducing the overuse of broad-spectrum antibiotics such as carbapenems, but their impact remains unclear. We compared the use of carbapenems between paediatric and adult subjects admitted to a French tertiary hospital and described the intervention of an antibiotic stewardship team (AST). As part of AST routine activity, all adult and paediatric patients receiving carbapenems are identified in real time using a computer-generated alert system and reviewed by the AST. Data associated with carbapenem prescriptions were extracted for 2 years (2014-2015) and were compared between paediatric and adult wards. Prescription appropriateness (i.e. no clinically suitable narrower spectrum alternative to carbapenem for de-escalation) and AST intervention were analysed. In total, 775 carbapenem prescriptions for 291 children and 262 adults were included. Most patients (95%) had a comordity and 52% had known recent carriage of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBLE). Most carbapenem prescriptions came from intensive care units (n = 269, 35%) and were initiated for urinary tract (n = 200, 27%), sepsis (n = 181, 25%), and lung (n = 153, 21%) infections. Carbapenems were initiated empirically in 537 (70%) cases, and an organism was isolated in 523 (67%) cases. Among the isolated organisms, 47% (n = 246) were ESBLE and 90% (n = 468) were susceptible to carbapenems, but an alternative existed in 61% (n = 320) of cases according to antibiotic susceptibility testing. Among prescriptions reviewed by the AST, 39% (n = 255) were considered non-appropriate and led to either antibiotic discontinuation (n = 47, 7%) or de-escalation (n = 208, 32%). Non-appropriate prescriptions were more frequent in paediatric wards (p = 0.01) and in microbiologically documented infections (p = 0.013), and less observed in immunocompromised patients (p = 0.009) or with a known ESBLE carriage (p < 0.001). Tailored stewardship programs are essential to better control carbapenem use and subsequent antimicrobial resistance.

A review of significance of Aspergillus detection in airways of ICU COVID-19 patients.

It is now well known that patients with SARS-CoV-2 infection admitted in ICU and mechanically ventilated are at risk of developing invasive pulmonary aspergillosis (IPA). Nevertheless, symptomatology of IPA is often atypical in mechanically ventilated patients, and radiological aspects in SARS-CoV-2 pneumonia and IPA are difficult to differentiate. In this context, the significance of the presence of Aspergillus in airway specimens (detected by culture, galactomannan antigen or specific PCR) remains to be fully understood. To decipher the relevance of the detection of Aspergillus, we performed a comprehensive review of all published cases of respiratory Aspergillus colonisation and IPA in COVID-19 patients. The comparison of patients receiving or not antifungal treatment allowed us to highlight the most important criteria for the decision to treat. The comparison of surviving and non-surviving patients made it possible to unveil criteria associated with mortality that should be taken into account in the treatment decision.

Pseudomonas aeruginosa bloodstream infections in children: a 9-year retrospective study.

P. aeruginosa bloodstream infection (BSI) is associated with high hospital mortality. Empirical combination therapy is commonly used, but its benefit remains debated. The purpose of this study was to describe in a paediatric population, demographical characteristics and outcome of children treated for P. aeruginosa BSI receiving either a combined or single antibacterial therapy. We performed a retrospective, single-centre, cohort study of hospitalized children with P. aeruginosa BSI from 2007 to 2015. A total of 118 bloodstream infections (BSI) were analysed (102 (86.4%) hospital-acquired, including 52 (44.1%) hospitalized in intensive care unit). In immunocompromised children, 52% of BSI episodes were recorded. Recent medical history revealed that 68% were hospitalized, 31% underwent surgery and 67% had a prior antibiotic therapy within the last 3 months. In-hospital mortality was similar for patients receiving single or combined anti-Pseudomonas therapy (p = 0.78). In multivariate analysis, independent risk factors for in-hospital mortality were neutropenia (OR = 6.23 [1.94-20.01], hospitalization in ICU (OR = 5.24 [2.04-13.49]) and urinary tract infection (OR = 4.40 [1.02-19.25]).Conclusion: P. aeruginosa BSI mainly occurred in immunocompromised children. Most infections were hospital-acquired and associated with high mortality. Combination therapy did not improve survival. What is Known: • P. aeruginosa bloodstream infection (BSI) is associated with high hospital mortality. Empirical combination therapy is commonly used but its benefit remains debated. What is New: • This is the largest cohort of Pseudomonas aeruginosa bacteraemia in children ever published. P. aeruginosa Bloodstream mainly occurred in immunocompromised children. Most infections were hospital-acquired and associated with high mortality. Combination therapy did not improve survival.

Prospective study on a fast-track training in psychiatry for medical students: the psychiatric hat game.

BACKGROUND: While medical students are losing interest in lectures in favor of other educational materials, many studies suggest the benefit of active learning, combined with gamified educational tools. The authors developed a psychiatric adaptation of the « Hat Game ¼. It was hypothesised that this game would increase both knowledge and motivation in medical students toward psychiatric semiology. The aim of the study was to assess the benefit of a Psychiatric Hat Game session for learning psychiatric symptoms in third-year medical students. Student performance was also evaluated at 3 months. METHODS: This gamified fast-track training consists of two teams and each team has to guess as many psychiatric semiology terms as possible using different techniques (i.e. speech, mime). The study involved a pre- and post-evaluation of knowledge (Multiple Choice Questions) and a satisfaction survey. Baseline, post-immediate, and three-months scores were compared by using Friedman analysis for paired samples. Comparisons of mean scores at two different times were performed by using Wilcoxon test for paired samples. RESULTS: One hundred and sixty-six students were proposed to take part in the study. Among them 129 completed the whole program (response rate = 77.7%). Mean scores measured at the three points in time were significantly different (p < 0.001, N = 129). Knowledge mean scores were significantly higher after the game than before (+ 28.6%, p < 0.001). Improvement was maintained 3 months after the game (+ 18.9%, p < 0.001). Satisfaction survey items highlighted that students enjoyed and would recommend this type of gamified training. CONCLUSIONS: The Psychiatric Hat Game improved knowledge of psychiatric semiology in medical students. Results suggest that it is a promising and efficient tool to playfully teach medical semiology, with transferable features, utility and acceptability from one medical field to another. This study contributes to the growing body of knowledge advocating for serious games and gamified training in medical education.

Screening for Intestinal Carriage of Extended-spectrum Beta-lactamase-producing Enterobacteriaceae in Critically Ill Patients: Expected Benefits and Evidence-based Controversies.

The rising burden of intensive care unit (ICU)-acquired infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) strengthens the requirement for efficient prevention strategies. The detection of intestinal carriage of ESBL-E through active surveillance cultures (ASC) and the implementation of contact precautions (CP) in carriers are currently advocated in most high-income countries, to prevent cross-transmission and subsequent ESBL-E infections in critically-ill patients. Yet, recent studies have challenged the benefit of ASC and CP in controlling the spread of ESBL-E in ICUs with high compliance to standard hygiene precautions and no ongoing outbreak of ESBL-producing Klebsiella pneumoniae or Enterobacter spp. Besides, given their debated performance to positively predict which patients are at risk of ESBL-E infections, ASC results appear of limited value to rationalize the empirical use of carbapenems in the ICU, emphasizing the urgent need for novel anticipatory and diagnostic approaches. This Viewpoint article summarizes the available evidence on these issues.

Elaboration of Consensus Clinical Endpoints to Evaluate Antimicrobial Treatment Efficacy in Future Hospital-acquired/Ventilator-associated Bacterial Pneumonia Clinical Trials.

BACKGROUND: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP. METHODS: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method. RESULTS: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement). CONCLUSIONS: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.

Prediction of methicillin-resistant Staphylococcus aureus bloodstream infection: do we need rapid diagnostic tests?

Staphylococcus aureus (SA) is the leading cause of bloodstream infection (BSI). The incidence of methicillin-resistant SA (MRSA) has decreased in France and Europe since one decade. Early and precise prediction of methicillin susceptibility is needed to improve probabilistic antibiotic therapy of MRSA-BSI. The aim of this study was to identify MRSA-BSI risk factors at admission and evaluate which patients need costly rapid diagnostic tests. A single-center retrospective descriptive study of all diagnosed SA-BSI was conducted in a French University Hospital between January 2015 and December 2016. All medical charts were reviewed. Univariate and multivariate analyses by a logistic regression model were performed on the data. We then build a prediction score of MRSA-BSI by assigning one point for each of the risk factor identified. During the study period, 151 SA-BSI were identified including 32 (21%) MRSA-BSI. In multivariate analysis, three factors were associated with MRSA-BSI: coming from long-term care facility, known previous MRSA colonization and/or infection, and chronic renal disease. Among our population, respectively, 5% and 100% had a MRSA-BSI when no or three risk factors were identified. Therefore, among the PCR performed, 43 (96%) could be avoided according to our clinical score. In our study, methicillin-susceptible SA and MRSA-BSI can be predictable by counting MRSA risk factors. This prediction rule could avoid the use of expensive rapid diagnostic tests. Prospective studies and prediction rules could help physicians to predict SA-BSI susceptibility to improve appropriate empiric therapy choice.

Is systematic fecal carriage screening of extended-spectrum beta-lactamase-producing Enterobacteriaceae still useful in intensive care unit: a systematic review.

BACKGROUND: Extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) are disseminating worldwide leading to increased hospital length of stay and mortality in intensive care units (ICU). ESBL-E dissemination was first due to outbreaks in hospital settings which led to the implementation of systematic fecal carriage screening to improve hygiene procedures by contact precautions. ESBLs have since spread in the community, and the relevance of contact precautions is questioned. ESBL-E dissemination led to an overuse of carbapenems triggering the emergence of carbapenem-resistant Enterobacteriaceae. Empirical antimicrobial therapy based on ESBL-E fecal carriage has been proposed but is debated as it could increase the consumption of carbapenems among ESBL-E carriers without any clinical benefit. Finally, selective decontamination among ESBL-E fecal carriers is evoked to decrease the risk for subsequent ESBL-E infection, but its efficacy remains debated. We propose to systematically review the evidence to recommend or not such systematic ESBL-E fecal carriage screening in adult ICU. METHODS: Every article focusing on ESBL-E and ICU available on the MEDLINE database was assessed. Articles were included if focusing on cross-transmission, efficacy of hygiene procedures, link between ESBL-E colonization and infection or guidance of empirical therapy or selective decontamination efficacy. RESULTS: Among 330 articles referenced on PubMed, 39 abstracts were selected for full-text assessment and 25 studies were included. Systematic screening of ESBL-E fecal carriage to guide contact precautions do not seem to decrease the rate of ESBL-E cross-transmission. It has a very good negative predictive value for subsequent ESBL-E infections but a positive predictive value between 40 and 50% and so does not help to spare carbapenems. Cessation of ESBL-E carriage systematic screening could decrease the use of carbapenems in ICU without any clinical harm. Nevertheless, further studies are needed to validate these results from monocentric before-after study. Selective decontamination strategy applied to ESBL-E fecal carriers could be helpful, but available data are conflicting. CONCLUSION: Current knowledge lacks of high-quality evidence to strongly recommend in favor of or against a systematic ESBL-E fecal carriage screening policy for ICU patients in a non-outbreak situation. Further evaluation of selective decontamination or fecal microbiota transplantation among ESBL-E fecal carriers is needed.

Diabetes was the only comorbid condition associated with mortality of invasive pneumococcal infection in ICU patients: a multicenter observational study from the Outcomerea research group.

PURPOSES: Streptococcus pneumoniae is a leading pathogen of severe community, hospital or nursing facility infections. We sought to describe characteristics of invasive pneumococcal infection (IPI) and pneumonia (due to the high mortality of intensive care-associated pneumonia) and to report outcomes according to various types of comorbidity. METHODS: Multicenter observational cohort study on the prospective Outcomerea database, including adult patients, with a hospital stay < 48 h before ICU admission and a documented IPI within the first 72 h of ICU admission. Comorbid conditions were defined according to the Knaus and Charlson classification. RESULTS: Of the 20,235 patients, 5310 (26.4%) had an invasive infection, including 560/5,310 (10.6%) who had an IPI. The ICU 28-day mortality was 109/560 (19.8%). Four factors were independently associated with mortality: SOFA day 1-2: [hazard ratio (HR) 1.21; 95% confidence interval (95% CI) 1.15-1.27, p < 0.001]; maximum lactate level day 1-2: (HR 1.07, 95% CI 1.02-1.12, p = 0.006); diabetes mellitus: (HR 1.91, 95% CI 1.23-3.03, p = 0.006) and appropriate antibiotics (HR 0.28, 95% CI 0.15-0.50, p < 0.001). Comparable results were obtained when other comorbid conditions were forced into the model. Diabetes impact was more pronounced in case of micro- or macro-angiopathy (HR 4.17, 95%CI 1.68-10.54, p = 0.003), in patients ≥ 65 years old (HR 2.59, 95% CI 1.56-4.28, < 0.001) and in those with body mass index (BMI) < 25 kg/m2 (HR 2.11, 95% CI 1.10-4.06, p = 0.025). CONCLUSIONS: Diabetes mellitus was the only comorbid condition which independently influenced mortality in patients with IPI. Its impact was more pronounced in patients with complications, aged ≥ 65 years and with BMI < 25 kg/m2.

Contact Precautions for Preventing Nosocomial Transmission of Extended-Spectrum ß Lactamase-Producing Escherichia coli: A Point/Counterpoint Review.

Contact precautions have been recommended for hospitalized patients colonized or infected with extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-EC). Despite such recommendations, a steady, worldwide increase of ESBL-EC has been reported. We discuss arguments in favor of and against contact precautions for ESBL-EC carriers. Healthcare settings with high ESBL-EC colonization pressure, extended hospital stay, and close contact between patients may serve as amplification platforms, further accelerating transmission. However, the evidence base for justifying the implementation of contact precautions for all ESBL-EC carriers remains weak. Until more high-level evidence is available, we support the attitude that hospitals and countries should carefully evaluate their decision on whether to implement contact precautions for ESBL-EC carriers. It is likely that a majority of patients and wards do not need to rely on contact precautions for preventing nosocomial ESBL-EC transmission in nonepidemic settings, without harming patient safety, providing sufficient compliance with standard precautions and ongoing surveillance.

Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials.

BACKGROUND: Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs. METHODS: A search (Pubmed-Embase-ICAAC-ECCMID) of all RCTs published between 1994 and 2016 comparing antimicrobial treatment for HAP/VAP in the intensive care unit was conducted. The populations enrolled, inclusion/exclusion criteria, statistical design and endpoints assessed were recorded. All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened. RESULTS: From the 93 abstracts reviewed, 39 potentially relevant studies were inspected, leading to 27 studies being included. As expected, illness severity or the proportion with VAP (27-100%) differed greatly among the enrolled populations. The HAP/VAP definition used various clinical and biological criteria, and only 55% of studies required a microbiological sample. The mandatory duration of prior hospital stay was variable; the mechanical ventilation duration was an inclusion criterion in only 41% of VAP studies. Nine studies had non-inferiority design, but nine studies (33%) did not have a pre-specified statistical hypothesis. Clinical cure was the primary endpoint in 24 studies, but was recorded in several populations or as the co-primary endpoint in 13 studies. The definition of clinical cure and the timing of its assessment greatly differed. This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened. CONCLUSION: Our study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the ICU. There was significant heterogeneity in enrollment criteria, endpoints and statistical design, which may influence the ability of studies to demonstrate differences between studied drugs.

How Should We Treat Hospital-Acquired and Ventilator-Associated Pneumonia Caused by Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae?

Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) due to extended-spectrum ß-lactamase­producing Enterobacteriaceae (ESBL-PE) represent a growing problem. Indeed, ESBL-PE is endemic in many countries, and 5 to 25% of intensive care unit (ICU) patients are ESBL-PE carrier on ICU admission. ESBL-PE HAP/VAP is associated with a higher mortality than HAP/VAP due to susceptible Enterobacteriaceae because the resistance profile decreases the adequacy rate of empiric therapy. ESBL-PE should be considered in the empirical treatment in case of the high burden of ESBL-PE in the unit, in the case of previous ESBL-PE colonization, when the HAP/VAP occurs late, and in patients with shock. A negative active systematic surveillance culture on rectal swab reduced the risk of ESBL-PE VAP to less than 1%. Rapid diagnostic tests are now able to confirm the presence of ESBL-PE in VAP within 24 hours; new molecular methods will provide results within few hours.Adequate treatment usually required carbapenems. The alternative ß-lactams such as ß-lactams/ß-lactamases inhibitor combinations could be proposed as a step-down therapy according to the antibiotic susceptibility result. Optimization of pharmacokinetics requires high dosage and continuous or prolonged infusions for ß-lactams. When the patient is stabilized, a therapy of duration 7 to 8 days is recommended.

A Systematic Review of the Definitions, Determinants, and Clinical Outcomes of Antimicrobial De-escalation in the Intensive Care Unit.

Antimicrobial de-escalation (ADE) is a strategy to reduce the spectrum of antimicrobials and aims to prevent the emergence of bacterial resistance. We present a systematic review describing the definitions, determinants and outcomes associated with ADE. We included 2 randomized controlled trials and 12 cohort studies. There was considerable variability in the definition of ADE. It was more frequently performed in patients with broad-spectrum and/or appropriate antimicrobial therapy (P= .05 to .002), when more agents were used (P= .002), and in the absence of multidrug-resistant pathogens (P< .05). Where investigated, lower or improving severity scores were consistently associated with ADE (P= .04 to <.001). The pooled effect of ADE on mortality is protective (relative risk, 0.68; 95% confidence interval, .52-.88). Because the determinants of ADE are markers of clinical improvement and/or of lower risk of treatment failure this effect on mortality cannot be retained as evidence. None of the studies were designed to investigate the effect of ADE on antimicrobial resistance.