Neisseria gonorrhoeae treatment failure to the recommended antibiotic regimen-Québec, Canada, 2015-19.

OBJECTIVE: To describe Neisseria gonorrhoeae treatment failure to the recommended antimicrobial regimens (azithromycin, cefixime and ceftriaxone). METHODS: Our study was a longitudinal analysis of treatment failures from an observational open cohort of gonococcal infection cases collected in Québec, Canada (n = 2547) between September 2015 and December 2019. Epidemiological and clinical data were collected using a self-administered questionnaire, direct case interviews and chart reviews. Antimicrobial susceptibility testing was performed using the agar dilution method. To be retained as a treatment failure, cases must have had (i) a laboratory-confirmed gonococcal infection; (ii) a documented treatment; (iii) a positive test of cure (TOC) performed within a defined period and (iv) no sexual contact (vaginal, oral or anal), even protected with a condom, between the beginning of treatment and the positive TOC. A broader definition, including suspected cases, was also examined. RESULTS: Among 1593 cases where a TOC was performed, 83 had a positive TOC: 11 were retained as treatment failure, and 6 were considered suspected cases (overall = 17/1593; 1.1%). Possible explanations for retained or suspected treatment failure included resistance to the antibiotics used for treatment (n = 1), pharyngeal infection (n = 9, of which 5 had been treated with ceftriaxone and 4 with other regimens); and azithromycin monotherapy (n = 1). Some cases had more than one potential explanation. CONCLUSIONS: Treatment failure occurred in 1.1% of cases of Neisseria gonorrhoeae infection for which a TOC was performed, including some cases of pharyngeal infection treated with ceftriaxone.

Genomic investigation of the most common Streptococcus pneumoniae serotypes causing invasive infections in Canada: the SAVE study, 2011-2020.

OBJECTIVES: To investigate the lineages and genomic antimicrobial resistance (AMR) determinants of the 10 most common pneumococcal serotypes identified in Canada during the five most recent years of the SAVE study, in the context of the 10-year post-PCV13 period in Canada. METHODS: The 10 most common invasive Streptococcus pneumoniae serotypes collected by the SAVE study from 2016 to 2020 were 3, 22F, 9N, 8, 4, 12F, 19A, 33F, 23A and 15A. A random sample comprising ∼5% of each of these serotypes collected during each year of the full SAVE study (2011-2020) were selected for whole-genome sequencing (WGS) using the Illumina NextSeq platform. Phylogenomic analysis was performed using the SNVPhyl pipeline. WGS data were used to identify virulence genes of interest, sequence types, global pneumococcal sequence clusters (GPSC) and AMR determinants. RESULTS: Of the 10 serotypes analysed in this study, six increased significantly in prevalence from 2011 to 2020: 3, 4, 8, 9N, 23A and 33F (P ≤ 0.0201). Serotypes 12F and 15A remained stable in prevalence over time, while serotype 19A decreased in prevalence (P < 0.0001). The investigated serotypes represented four of the most prevalent international lineages causing non-vaccine serotype pneumococcal disease in the PCV13 era: GPSC3 (serotypes 8/33F), GPSC19 (22F), GPSC5 (23A) and GPSC26 (12F). Of these lineages, GPSC5 isolates were found to consistently possess the most AMR determinants. Commonly collected vaccine serotypes 3 and 4 were associated with GPSC12 and GPSC27, respectively. However, a more recently collected lineage of serotype 4 (GPSC192) was highly clonal and possessed AMR determinants. CONCLUSIONS: Continued genomic surveillance of S. pneumoniae in Canada is essential to monitor for the appearance of new and evolving lineages, including antimicrobial-resistant GPSC5 and GPSC162.

Increasing Azithromycin Resistance in Neisseria gonorrhoeae Due to NG-MAST 12302 Clonal Spread in Canada, 2015 to 2018.

Azithromycin-resistant (AZIR) gonorrhea has been steadily increasing in Canada over the past decade, which is cause for alarm, as azithromycin (AZI) has been part of the combination therapy recommended by the Canadian Guidelines on Sexually Transmitted Infections (CGSTI) since 2012. Neisseria gonorrhoeae with AZI MICs ≥1 mg/L collected between 2015 and 2018 as part of the Gonococcal Antimicrobial Surveillance Program-Canada underwent antimicrobial susceptibility testing, molecular typing, and whole-genome sequencing. Regional, demographic, and clinical isolation site comparisons were made to aid in our understanding of AZI susceptibility trending. We identified 3,447 N. gonorrhoeae with AZI MICs of ≥1 mg/L in Canada, which increased from 6.3% in 2015 to 26.5% of isolates in 2018. Central Canada had the highest proportion, rising from 9.2% in 2015 to 31.2% in 2018. We identified 273 different N. gonorrhoeae multiantigen sequence types (NG-MAST) among these isolates, with ST-12302 the most prevalent (50.9%). Whole-genome sequencing identified the Neisseria lactamica-like mosaic mtr locus as the mechanism of AZIR in isolates of ST-12302 and isolates genetically similar (differing by ≤5 bp), designated the ST-12302 genogroup, accounting for 65.2% of study isolates which were originally identified in central Canada but spread to other regions by 2018. Genomic analysis indicated that AZIR in Canadian N. gonorrhoeae expanded rapidly due to clonal spread of the ST-12302 genogroup. The rapid expansion of this AZIR clonal group in all regions of Canada is of concern. CGSTI are currently under review to address the increase in AZIR in Canada.

Linear Regression Equations To Predict ß-Lactam, Macrolide, Lincosamide, and Fluoroquinolone MICs from Molecular Antimicrobial Resistance Determinants in Streptococcus pneumoniae.

Antimicrobial resistance in Streptococcus pneumoniae represents a threat to public health, and monitoring the dissemination of resistant strains is essential to guiding health policy. Multiple-variable linear regression modeling was used to determine the contributions of molecular antimicrobial resistance determinants to antimicrobial MICs for penicillin, ceftriaxone, erythromycin, clarithromycin, clindamycin, levofloxacin, and trimethoprim-sulfamethoxazole. Training data sets consisting of Canadian S. pneumoniae isolates obtained from 1995 to 2019 were used to generate multiple-variable linear regression equations for each antimicrobial. The regression equations were then applied to validation data sets of Canadian (n = 439) and U.S. (n = 607 and n = 747) isolates. The MICs for ß-lactam antimicrobials were fully explained by amino acid substitutions in motif regions of the penicillin binding proteins PBP1a, PPB2b, and PBP2x. Accuracies of predicted MICs within 1 doubling dilution to phenotypically determined MICs were 97.4% for penicillin, 98.2% for ceftriaxone, 94.8% for erythromycin, 96.6% for clarithromycin, 98.2% for clindamycin, 100% for levofloxacin, and 98.8% for trimethoprim-sulfamethoxazole, with an overall sensitivity of 95.8% and specificity of 98.0%. Accuracies of predicted MICs to the phenotypically determined MICs were similar to those of phenotype-only MIC comparison studies. The ability to acquire detailed antimicrobial resistance information directly from molecular determinants will facilitate the transition from routine phenotypic testing to whole-genome sequencing analysis and can fill the surveillance gap in an era of increased reliance on nucleic acid assay diagnostics to better monitor the dynamics of S. pneumoniae.

The relationship between social deprivation and a frailty index of cumulative deficits in French middle-aged caregivers.

BACKGROUND: The Institut Pasteur de Lille, in the north of France, has implemented a large, multidisciplinary health check, which aims to identify frailty in middle-aged caregivers. We aimed to construct an adapted frailty index of cumulative deficit (FI-CD) and study the associated factors, in particular socioeconomic factors. METHODS: The cross-sectional study included caregivers aged 45 to 65. A 34-item FI-CD including deficits adapted to a middle-aged population (related to cognition and autonomy, dietetics, physical activity, comorbidities, functional signs, lab values and paraclinical examinations) was constructed in accordance with standard procedures. It was calculated as a ratio of deficits present out of the total number of possible deficits, giving a continuous score between 0 and 1. Scores > 0.25 and >  0.4 were classified as frailty and severe frailty, respectively. Univariate and multivariate associations were studied using linear regressions. RESULTS: One hundred and seventeen caregivers were included; among them, 111 were analyzed due to missing values. The mean FI-CD was 0.22 ± 0.08. Forty (36%) individuals were classified as frailty and three (2.7%) as severe frailty. In multivariate analysis, FI-CD was significantly associated with age (beta [95% confidence interval] = 0.005 [0.002; 0.009] per 1-year increase, p = 0.005) and social deprivation (beta = 0.054 [0.007; 0.102], p = 0.025). A significant interaction was observed between and age and social deprivation (p = 0.036). The adjusted relationship between FI-CD and age was beta = 0.010 [0.002; 0.019], p = 0.017 in precarious caregivers, and beta = 0.003 [- 0.001; 0.007], p = 0.19 in non-precarious caregivers. CONCLUSIONS: The study suggested that the 34-item FI-CD could have clinical utility in the management of middle-aged caregivers. Social deprivation appeared as an important factor associated with frailty, highlighting the importance of early care and social support for precarious caregivers.

Assessment of Piperacillin-Tazobactam-Meropenem Synergy against Serine Carbapenemase-Producing Enterobacterales Using Time-Kill Assays.

Synergy between piperacillin-tazobactam and meropenem against KPC-producing Klebsiella pneumoniae was recently demonstrated. We sought to test the combination against a broader range of serine carbapenemase producers. We tested the combination against 10 KPC-producing Escherichia coli and 10 OXA-48 family-producing K. pneumoniae isolates. Antibiotic concentrations used are achievable in critically ill patients. The combination was synergistic against 7 of 10 KPC producers and 9 of 10 OXA-48 producers. There was no synergy detected in control isolates producing NDM-1.

Equations To Predict Antimicrobial MICs in Neisseria gonorrhoeae Using Molecular Antimicrobial Resistance Determinants.

The emergence of Neisseria gonorrhoeae strains that are resistant to azithromycin and extended-spectrum cephalosporins represents a public health threat, that of untreatable gonorrhea infections. Multivariate regression modeling was used to determine the contributions of molecular antimicrobial resistance determinants to the overall antimicrobial MICs for ceftriaxone, cefixime, azithromycin, tetracycline, ciprofloxacin, and penicillin. A training data set consisting of 1,280 N. gonorrhoeae strains was used to generate regression equations which were then applied to validation data sets of Canadian (n = 1,095) and international (n = 431) strains. The predicted MICs for extended-spectrum cephalosporins (ceftriaxone and cefixime) were fully explained by 5 amino acid substitutions in PenA, A311V, A501P/T/V, N513Y, A517G, and G543S; the presence of a disrupted mtrR promoter; and the PorB G120 and PonA L421P mutations. The correlation of predicted MICs within one doubling dilution to phenotypically determined MICs of the Canadian validation data set was 95.0% for ceftriaxone, 95.6% for cefixime, 91.4% for azithromycin, 98.2% for tetracycline, 90.4% for ciprofloxacin, and 92.3% for penicillin, with an overall sensitivity of 99.9% and specificity of 97.1%. The correlations of predicted MIC values to the phenotypically determined MICs were similar to those from phenotype MIC-only comparison studies. The ability to acquire detailed antimicrobial resistance information directly from molecular data will facilitate the transition to whole-genome sequencing analysis from phenotypic testing and can fill the surveillance gap in an era of increased reliance on nucleic acid assay testing (NAAT) diagnostics to better monitor the dynamics of N. gonorrhoeae.

Arrival of the rare carbapenemase OXA-204 in Canada causing a multispecies outbreak over 3 years.

OBJECTIVES: To investigate a persistent multispecies OXA-204 outbreak occurring simultaneously in multiple distant hospitals in the province of Quebec, Canada. METHODS: OXA-204 carbapenemase-producing Enterobacterales (CPE) isolated from multiple hospitals between January 2016 and October 2018 were included in the study. An epidemiological inquiry was conducted in order to elucidate possible transmission routes and a putative source. Isolates were characterized by standardized antibiotic susceptibility testing and by WGS, using Illumina short-read data and MinION long-read data. RESULTS: The outbreak comprised 65 patients and 82 isolates from four hospital sites. Most patients were ≥65 years old, had multiple comorbidities and had received antibiotics recently. The infection to colonization ratio was 1:20. No persistent environmental reservoir was identified. The most frequent organism was Citrobacter freundii (n = 78), followed by Klebsiella spp. (n = 3) and Escherichia coli (n = 1). WGS analysis showed 77/78 C. freundii isolates differing by 0-26 single nucleotide variants (SNVs). Results of WGS analysis showed blaOXA-204 was present on three plasmids types (IncX1, IncA/C2 and IncFII/FIB/A/C2) and on a prophage. All C. freundii isolates harboured multiple copies of blaOXA-204, both on the chromosome and a plasmid. Plasmid IncFII/FIB/A/C2 was observed in all three species. CONCLUSIONS: Transfer of OXA-204 plasmids likely occurred between species within the same patient, highlighting the plasticity of these plasmids and potential for widespread dissemination. OXA-204 carbapenemase has been introduced into Quebec and has rapidly disseminated. Although the infection to colonization ratio was low in this outbreak, this carbapenemase has been associated with severe infection elsewhere.

Whole genome sequencing to study the phylogenetic structure of serotype a Haemophilus influenzae recovered from patients in Canada.

This study examined the phylogenetic structure of serotype a Haemophilus influenzae (Hia) isolates recovered from patients in Canada. Hia isolates from 490 separate patients and an American Type Culture Collection (ATCC) strain were analyzed by multilocus sequence typing (MLST), with 18 different sequence types (STs) identified. Most (85.7%) Hia patient isolates were typed as ST-23 and another 12.7% belonged to 14 different STs with 6, 5, or 4 MLST gene loci related to ST-23 (ST-23 complex). Core genome single-nucleotide variation phylogeny (SNVPhyl) on whole genome sequence (WGS) data of 121 Hia patient isolates representing all identified STs and the ATCC strain revealed 2 phylogenetic populations, with all the ST-23 complex isolates within 1 population. The other phylogenetic population contained only the ATCC strain and 3 patient isolates. Concatenated hitABC sequences retrieved from WGS data and analyzed by MEGA (Molecular Evolutionary Genetic Analysis) alignment confirmed the phylogeny obtained by SNVPhyl. The sodC gene was found only in isolates in the minor phylogenetic population. The 2 phylogenetic populations of the Canadian Hia isolates are similar to the 2 clonal divisions described for serotype b H. influenzae. Combining MLST, core SNVPhyl, and hitABC gene sequence alignment showed that most (99.4%) Canadian Hia patient isolates belonged to 1 major phylogenetic population.

Genetic Mechanisms behind the Spread of Reduced Susceptibility to Azithromycin in Shigella Strains Isolated from Men Who Have Sex with Men in Québec, Canada.

We analyzed 254 Shigella species isolates collected in Québec, Canada, during 2013 and 2014. Overall, 23.6% of isolates showed reduced susceptibility to azithromycin (RSA) encoded by mphA (11.6%), ermB (1.7%), or both genes (86.7%). Shigella strains with RSA were mostly isolated from men who have sex with men (68.8% or higher) from the Montreal region. A complete sequence analysis of six selected plasmids from Shigella sonnei and different serotypes of Shigella flexneri emphasized the role of IS26 in the dissemination of RSA.

Genomic Investigation of the Emergence of Invasive Multidrug-Resistant Salmonella enterica Serovar Dublin in Humans and Animals in Canada.

Salmonella enterica subsp. enterica serovar Dublin is a zoonotic pathogen that often leads to invasive bloodstream infections in humans that are multidrug resistant. Described here are the results of Canadian national surveillance of S Dublin from 2003 to 2015 in humans and bovines, principally collected through the Canadian Integrated Program for Antibiotic Resistance Surveillance (CIPARS). An increase in human infections due to multidrug-resistant (MDR) S Dublin was observed in 2010, many of which were bloodstream infections. Phylogenomic analysis of human and bovine isolates revealed a closely related network that differed by only 0 to 17 single nucleotide variants (SNVs), suggesting some potential transmission between humans and bovines. Phylogenomic comparison of global publicly available sequences of S Dublin showed that Canadian isolates clustered closely with those from the United States. A high correlation between phenotypic and genotypic antimicrobial susceptibility was observed in Canadian isolates. IS26 replication was widespread among U.S. and Canadian isolates and caused the truncation and inactivation of the resistance genes strA and blaTEM-1B A hybrid virulence and MDR plasmid (pN13-01125) isolated from a Canadian S Dublin isolate was searched against NCBI SRA data of bacteria. The pN13-01125 coding sequences were found in 13 Salmonella serovars, but S Dublin appears to be a specific reservoir. In summary, we have observed the rise of invasive MDR S Dublin in humans in Canada and found that they are closely related to bovine isolates and to American isolates in their mobile and chromosomal contents.

In vitro synergy of ß-lactam combinations against KPC-producing Klebsiella pneumoniae strains.

BACKGROUND: Double carbapenem therapy has been promoted as an alternative treatment for infections due to carbapenemase-producing Enterobacteriaceae where carbapenemase inhibitors are unavailable or when other agents have demonstrated toxicity with equally limited evidence. The capacity of other ß-lactams and ß-lactamase inhibitors to provide synergistic activity with carbapenems is unclear. OBJECTIVES: This study sought to investigate the in vitro synergistic potential of other ß-lactam/ß-lactamase combinations with meropenem against KPC producers. METHODS: Time-kill assays were performed on 24 unique strains of KPC-producing Klebsiella pneumoniae. Combinations evaluated included meropenem or imipenem with one of the following: ertapenem, piperacillin/tazobactam or ceftolozane/tazobactam. Concentrations used for each drug were those considered physiologically attainable in patients with a time above the concentration exceeding 40%-50% of the dose interval. Combinations were considered to be synergistic when they reduced bacterial cfu/mL by ≥2 log10 at 24 h as compared with the single most active agent. RESULTS: The combination of piperacillin/tazobactam with meropenem was found to be synergistic against 70.8% of the isolates, followed by ertapenem with meropenem (58.3%) and ceftolozane/tazobactam with meropenem (41.7%). The piperacillin/tazobactam combination was found to be more bactericidal than the other combinations, with 58.3% of isolates demonstrating a ≥4 log10 cfu/mL reduction at 24 h, as compared with 37.5% for ertapenem and 20.8% for ceftolozane/tazobactam combinations. CONCLUSIONS: The combination of piperacillin/tazobactam with meropenem may be a potential therapy against KPC-producing K. pneumoniae when other therapies are unavailable or prohibitively toxic.

Ceftriaxone-Resistant Neisseria gonorrhoeae, Canada, 2017.

We identified a ceftriaxone-resistant Neisseria gonorrhoeae isolate in a patient in Canada. This isolate carried the penA-60 allele, which differs substantially from its closest relative, mosaic penA XXVII (80% nucleotide identity). Epidemiologic and genomic data suggest spread from Asia. Antimicrobial susceptibility surveillance helps prevent spread of highly resistant N. gonorrhoeae strains.

Cooperative Recognition of Internationally Disseminated Ceftriaxone-Resistant Neisseria gonorrhoeae Strain.

Ceftriaxone remains a first-line treatment for patients infected by Neisseria gonorrhoeae in most settings. We investigated the possible spread of a ceftriaxone-resistant FC428 N. gonorrhoeae clone in Japan after recent isolation of similar strains in Denmark (GK124) and Canada (47707). We report 2 instances of the FC428 clone in Australia in heterosexual men traveling from Asia. Our bioinformatic analyses included core single-nucleotide variation phylogeny and in silico molecular typing; phylogenetic analysis showed close genetic relatedness among all 5 isolates. Results showed multilocus sequence type 1903; N. gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) 233; and harboring of mosaic penA allele encoding alterations A311V and T483S (penA-60.001), associated with ceftriaxone resistance. Our results provide further evidence of international transmission of ceftriaxone-resistant N. gonorrhoeae. We recommend increasing awareness of international spread of this drug-resistant strain, strengthening surveillance to include identifying treatment failures and contacts, and strengthening international sharing of data.

Characterization of OXA-48-like carbapenemase producers in Canada, 2011-14.

Objectives: Since the first identification of the OXA-48 carbapenemase in 2001, Enterobacteriaceae harbouring OXA-48-like enzymes have been reported globally. Here, we applied WGS to characterize the molecular epidemiology of these bacterial isolates. Methods: Enterobacteriaceae non-susceptible to carbapenems isolated from patients between 2011 and 2014 were voluntarily submitted to the Canadian National Microbiology Laboratory where they were screened for carbapenemase genes. WGS was conducted on OXA-48-like producers using the Illumina MiSeq platform. WGS data were used for single nucleotide variant (SNV) analysis, MLST analysis, detection of resistance genes and partial plasmid characterization. Susceptibilities were determined using Vitek2 and Etest. Patient data provided from sites were reviewed. Results: Sixty-seven non-duplicated cases were identified among Escherichia coli (n = 21) and Klebsiella pneumoniae (n = 46). Recent international travel was observed in 40.4% of cases. OXA-181 (52.2%) and OXA-48 (31.3%) were the most common variants, one E. coli OXA-48 producer was found to harbour the acquired colistin resistance gene mcr-1. The dominant STs were ST38 and ST410 in E. coli and ST14 in K. pneumoniae. Three common plasmid types were observed among isolates: IncL/M associated with OXA-48 producers, and ColKP3 and IncX3 associated with OXA-181/232 producers. Conclusions: Enterobacteriaceae with OXA-48-like carbapenemases are emerging in Canada. This study highlights the complexity of OXA-48-types identified in Canada owing to travel and the successful clones and plasmids harbouring the OXA-48-like enzyme.

Molecular characterization of predominant Streptococcus pneumoniae serotypes causing invasive infections in Canada: the SAVE study, 2011-15.

Objectives: This study characterized the 11 most predominant serotypes of invasive Streptococcus pneumoniae infections collected by the annual SAVE study in Canada, between 2011 and 2015. Methods: A subset of the 11 most predominant serotypes (7F, 19A, 22F, 3, 12F, 11A, 9N, 8, 33F, 15A and 6C) collected by the SAVE study was analysed using PFGE and MLST, as well as PCR to identify pilus-encoding genes. WGS analyses were performed on a subset of the above isolates plus a random selection of background strains. Results: Of the predominant serotypes analysed, 7F, 33F and 19A were obtained more commonly from children <6 years of age, whereas 15A, 6C, 22F and 11A were more common in adults >65 years of age. Pneumococcal pilus PI-1 was identified in antimicrobial-susceptible serotype 15A (61/212) and <10% of 6C isolates (16/188). PI-2 was found in serotype 7F (683/701) and two-thirds of 11A isolates (162/241). Only serotype 19A-ST320 possessed both pili. Molecular and phylogenetic analyses identified serotypes 19A, 15A, 6C, 9N and 33F as highly diverse, whereas 7F, 22F and 11A demonstrated clonality. Antimicrobial resistance determinants were common within diverse serotypes, and usually similar within a clonal complex. Conclusions: Despite successful use of conjugate vaccines, S. pneumoniae remains a highly diverse organism in Canada. Several predominant serotypes, both antimicrobial susceptible and MDR, have demonstrated rapid clonal expansion or an increase in diversity. As S. pneumoniae continues to evolve in Canada, WGS will be a necessary component in the ongoing surveillance of antimicrobial-resistant and expanding clones.

A Comparison of Real-Time Polymerase Chain Reaction Assays for the Detection of Antimicrobial Resistance Markers and Sequence Typing From Clinical Nucleic Acid Amplification Test Samples and Matched Neisseria gonorrhoeae Culture.

Real-time polymerase chain reaction (PCR) assays to detect antimicrobial resistance-associated mutations were tested on Neisseria gonorrhoeae-positive clinical samples with matched isolates. Of the nucleic acid amplification tests/cultures, 87.7% (64/73), 98.6% (72/73), and 98.4% (62/63) predicted cephalosporin, ciprofloxacin, and azithromycin susceptibilities, respectively. N. gonorrhoeae multiantigen sequence type was correctly predicted for 98.7% (79/80), and 13 of 58 N. gonorrhoeae-negative specimens showed false-positive results.

[Attractiveness of France for international clinical research: 8th survey conducted by Leem (French association for pharmaceutical companies)]. / Attractivité de la France pour la recherche clinique internationale : résultats de la 8e enquête du Leem.

The Leem (French association of pharmaceutical companies) has conducted the eighth survey on attractiveness of France for clinical research. It serves to measure France's global competitiveness for international clinical trials and assess its strengths and areas of excellence. It also highlights the potential for progress and emerging trends at a time when the regulatory environment in France and Europe is undergoing change. This survey has been updated every two years since 2002 using the same methodology. It assesses the current status of research undertaken in France by the pharmaceutical industry between January 1st 2014 and December 31st 2015. Thirty companies (62% of the French market) have participated in this 8th survey which involved 3474 centers (versus 2860 in 2014) and 16,622 patients (versus 14,634 in 2014) enrolled in France across 586 clinical trials (versus 613 in 2014). This survey shows a reduction in the number of phase I and phase II trials. It also confirms that the studies conducted in France are primarily concerned with oncology (45%). Despite improvements across hospital contracts times (due to the adoption of the sole agreement) and performance indicators in trials (such as the number of patients enrolled by center), trial setup times in France are still overly lengthy (with stable times by French authorities). Ensuring that clinical research remains a priority issue for country is crucial for patients because of rapid access to innovation but also for the vitality of the French economy. Constructive dialogue with stakeholders on the subject of clinical research is essential to enhance the attractiveness of France and to improve the continuum between research, innovation and care.

Impact of an Immunization Campaign to Control an Increased Incidence of Serogroup B Meningococcal Disease in One Region of Quebec, Canada.

Background: Invasive meningococcal disease (IMD) incidence increased in Quebec, starting in 2003, and was caused by a serogroup B sequence type 269 clone. The Saguenay-Lac-Saint-Jean (SLSJ) region was particularly affected with a rate of 3.4 per 100000 person-years in 2006-2013. In May 2014, an immunization campaign was launched in SLSJ, using the 4-component protein-based meningococcal vaccine (MenB-4C). We aimed to evaluate the impact of the campaign 2 years after its initiation. Methods: Immunization registry data and serogroup B invasive meningococcal disease (B-IMD) cases notified to public health authorities and confirmed by culture or polymerase chain reaction from July 1996 to December 2016 were analyzed, including a multivariate Poisson regression model of incidence rates. Results: By the end of the campaign, 82% of the 59000 targeted SLSJ residents between 2 months and 20 years of age had been immunized. Following the initiation of the campaign, no B-IMD case occurred among vaccinees, whereas 2 cases were reported among unvaccinated adult SLSJ residents, and a third case in an unvaccinated child who had stayed in the region during the week prior to disease onset, in 2015. B-IMD incidence decreased in all other regions in the years 2015-2016 but sporadic cases continued to occur. A multivariate analysis showed a significant effect of the campaign in the SLSJ region (relative B-IMD risk: 0.22; P = .04). Conclusions: Results suggest a high level of protection provided by MenB-4C following mass vaccination at regional level. This, along with reassuring safety data, supports the current recommendations for MenB-4C use for controlling outbreaks caused by clones covered by the vaccine.

Enterobacter cloacae Complex Isolates Harboring blaNMC-A or blaIMI-Type Class A Carbapenemase Genes on Novel Chromosomal Integrative Elements and Plasmids.

Carbapenem-resistant Enterobacter cloacae complex isolates submitted to a reference laboratory from 2010 to 2015 were screened by PCR for seven common carbapenemase gene groups, namely, KPC, NDM, OXA-48, VIM, IMP, GES, and NMC-A/IMI. Nineteen of the submitted isolates (1.7%) were found to harbor Ambler class A blaNMC-A or blaIMI-type carbapenemases. All 19 isolates were resistant to at least one carbapenem but susceptible to aminoglycosides, trimethoprim-sulfamethoxazole, tigecycline, and ciprofloxacin. Most isolates (17/19) gave positive results with the Carba-NP test for phenotypic carbapenemase detection. Isolates were genetically diverse by pulsed-field gel electrophoresis macrorestriction analysis, multilocus sequence typing, and hsp60 gene analysis. The genes were found in various Enterobacter cloacae complex species; however, blaNMC-A was highly associated with Enterobacter ludwigii Whole-genome sequencing and bioinformatics analysis revealed that all NMC-A (n = 10), IMI-1 (n = 5), and IMI-9 (n = 2) producers harbored the carbapenemase gene on EludIMEX-1-like integrative mobile elements (EcloIMEXs) located in the identical chromosomal locus. Two novel genes, blaIMI-5 and blaIMI-6, were harbored on different IncFII-type plasmids. Enterobacter cloacae complex isolates harboring blaNMC-A/IMI-type carbapenemases are relatively rare in Canada. Though mostly found integrated into the chromosome, some variants are located on plasmids that may enhance their mobility potential.