Integrated surveillance of antimicrobial resistance and antimicrobial use: Evaluation of the status in Canada (2014-2019).

OBJECTIVE: Integrated surveillance of antimicrobial resistance (AMR) and antimicrobial use (AMU) across One Health sectors is critically important for effective, evidence-based policy, stewardship, and control of AMR. Our objective was to evaluate progress towards achieving comprehensive, integrated AMR/AMU surveillance in Canada. MATERIALS AND METHODS: Based on an environmental scan, interviews of subject matter experts, and reports from the 2014 National Collaborating Centre for Infectious Diseases and the 2016 Canadian Council of Chief Veterinary Officers, we identified 8 core surveillance requirements and their specific components; the latter were assessed using a 2-way classification matrix, with 7 common elements ranked according to development stage. RESULTS: Components that mapped to requirements of a comprehensive, fully integrated AMR/AMU surveillance system were mostly in the lowest stages of development (Exploration or Program Adoption). However, both the establishment of the Canadian AMR Surveillance System integrated reporting and expansion of existing components under the Canadian Nosocomial Infection Surveillance Program and the Canadian Integrated Program for AMR Surveillance are improvements. Regardless, obvious gaps in Canadian AMR/AMU surveillance prevent this from being a comprehensive and integrated One Health program. CONCLUSION: Action is needed in 3 crucial areas: i) development of a complete, integrated AMR/AMU surveillance program, based on current success; ii) changes in Federal/Provincial/Territorial policies to require standardized AMR/AMU reporting; and iii) more resources for AMR/AMU surveillance (dedicated persons, funding, and enabling structures and policy). There is an urgent need for prioritization by Federal/Provincial/Territorial governments to address governance, leadership, and funding to create surveillance systems that inform stewardship and policy.

OBJECTIF: La surveillance intégrée de la résistance aux antimicrobiens (RAM) et de l'utilisation des antimicrobiens (UAM) dans les secteurs Une seule santé est d'une importance cruciale pour une politique, une gestion et une maitrise efficaces et fondées sur des preuves de la résistance aux antimicrobiens. Notre objectif était d'évaluer les progrès vers la réalisation d'une surveillance complète et intégrée de la RAM/UAM au Canada. MÉTHODES: Sur la base d'une analyse de l'environnement, d'entrevues d'experts en la matière et de rapports du Centre de collaboration nationale des maladies infectieuses de 2014 et du Conseil canadien des chefs vétérinaires de 2016, nous avons identifié huit exigences de surveillance de base et leurs composantes spécifiques ; ces derniers ont été évalués à l'aide d'une matrice de classification à deux voies, avec sept éléments communs classés selon le stade de développement. RÉSULTATS: Les composants correspondant aux exigences d'un système de surveillance de la RAM/UAM complet et entièrement intégré en étaient pour la plupart aux stades les plus bas de développement (Exploration ou Adoption de programme). Cependant, l'établissement du Système canadien de surveillance de la RAM et l'expansion des éléments existants dans le cadre du Programme canadien de surveillance des infections nosocomiales et du Programme intégré canadien de surveillance de la RAM constituent des améliorations. Quoi qu'il en soit, des lacunes évidentes dans la surveillance canadienne de la RAM/UAM l'empêchent d'être un programme Une seule santé complet et intégré. CONCLUSION: Des actions sont nécessaires dans trois domaines cruciaux : 1) le développement d'un programme de surveillance complet et intégré de la RAM/AMU, basé sur le succès actuel; 2) des changements aux politiques fédéralesprovinciales-territoriales pour exiger des rapports normalisés sur la RAM/UAM; et 3) davantage de ressources pour la surveillance de la RAM/UAM (personnes dédiées, financement, structures et politiques habilitantes). Il est urgent que les gouvernements fédéral-provincial-territorial établissent des priorités pour aborder la gouvernance, le leadership et le financement afin de créer des systèmes de surveillance qui éclairent la gouvernance et les politiques.(Traduit par Dr Serge Messier).

Vitamins and Minerals for Migraine Prophylaxis: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the findings of randomized controlled trials (RCTs) on the efficacy and safety of vitamins and minerals for migraine prophylaxis. METHODS: We systematically searched bibliographic databases and relevant websites for parallel and crossover RCTs reporting efficacy and/or safety of vitamins and/or minerals for migraine prophylaxis. Our primary outcomes were migraine frequency (number of attacks) and duration (hours). Secondary outcomes were severity (intensity), days with migraine, and adverse events. Meta-analysis was conducted when analyzable data were available from at least two trials. RESULTS: Eighteen placebo-controlled trials met our eligibility criteria. Only coenzyme Q10 and magnesium contributed to meta-analyses. In adults, compared with placebo, coenzyme Q10 did not significantly decrease migraine frequency (mean difference (MD) -0.44 (-2.14 to 1.26); I2 53%; 2 trials; 97 participants; moderate strength of the evidence), duration (MD -1.97 (-4.82 to 0.87); I2 0%; 2 trials; 97 participants; moderate strength of the evidence), or severity (ratio of means (RoM) -0.05 (-0.20 to 0.11); I2 0%; 2 trials; 97 participants). In adults, compared with placebo, magnesium did not significantly decrease migraine severity (RoM -0.17 (-0.36 to 0.02); I2 48%; 3 trials; 226 participants; low strength of the evidence). Meta-analysis of other vitamins and minerals, and other outcomes were not feasible due to a lack of sufficiently reported data. CONCLUSIONS: Based on insufficient evidence, it is unknown if coenzyme Q10 and magnesium are effective for migraine prophylaxis in adults. High-quality, adequately powered RCTs are needed to fully evaluate the efficacy and safety of vitamins and minerals for migraine prophylaxis.

Evolution and molecular characterization of macrolide-resistant Streptococcus pneumoniae in Canada between 1998 and 2008.

OBJECTIVES: Studies were performed to assess resistance mechanisms, multidrug resistance (MDR), genetic relatedness, serotype distribution, heptavalent pneumococcal conjugate vaccine (PCV7) coverage and pili virulence factors among macrolide-resistant Streptococcus pneumoniae (MRSP) isolated from respiratory samples submitted to hospital laboratories across Canada from 1998 to 2008. METHODS: Isolates of MRSP (n = 1518) collected by the national surveillance studies CROSS (Canadian Respiratory Organism Susceptibility Study; 1998-2006) and CANWARD (Canadian Ward Surveillance Study; 2007-08) were tested using the CLSI broth microdilution method to establish antimicrobial susceptibilities. PCR was used to detect macrolide resistance genes [mef(A) and erm(B)] and pili virulence factors (type 1 pili and type 2 pili), the Quellung reaction was used to identify serotypes and PFGE was used to determine genetic relatedness. RESULTS: The prevalence of MRSP increased from 8% in 1998 to 22% in 2008 (P = 0.0001). MRSP were 51% mef(A) positive, 36% erm(B) positive, 8% dual mef(A) and erm(B) positive and 5% mef(A) and erm(B) negative. Dual mef(A)- and erm(B)-positive isolates increased in prevalence from 3% in 1998 to 19% in 2008 (P = 0.001). The prevalence of PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) decreased from 67% in 1998 to 31% in 2008 (P = 0.0072). The prevalence of serotype 19A, a non-PCV7 serotype, increased by 15% from 1998 to 2008; isolates of serotype 19A were MDR, dual mef(A) and erm(B) positive, genetically related by PFGE and associated with the presence of pili virulence factors. CONCLUSIONS: From 1998 to 2008, respiratory isolates of MRSP in Canada increased significantly due primarily to the emergence and spread of serotypes 6A, 19A and other non-PCV7 serotypes.

Summary of the NACI Statement on Public Health Level Recommendations on the Use of Pneumococcal Vaccines in Adults, Including the Use of 15-valent and 20-valent Conjugate Vaccines.

Background: Age and certain medical/social conditions are risk factors for invasive pneumococcal disease (IPD). For prevention of IPD, the National Advisory Committee on Immunization (NACI) has recommended the 23-valent polysaccharide pneumococcal vaccine, PNEU-P-23, for adults 65 years of age and older and adults over 18 years of age living with certain underlying conditions. NACI has also recommended 13-valent conjugate pneumococcal vaccine, PNEU-C-13, for adults; however, in publicly funded programs, this recommendation is limited to individuals with risk factors for IPD. Two new conjugate vaccines, PNEU-C-15 and PNEU-C-20, have been authorized by Health Canada for prevention of IPD in adults. This article summarizes NACI public health recommendations for pneumococcal vaccines in adults given these new conjugate vaccines that provide additional serotype coverage over PNEU-C-13. Methods: Key studies evaluating the immunogenicity and safety of PNEU-C-15 and PNEU-C-20 were reviewed. The Grading of Recommendations, Assessment, Development and Evaluations framework methodology was used to assess the certainty of evidence. Results: The PNEU-C-15 and PNEU-C-20 vaccines showed comparable immune responses, and safety profiles for all mild, moderate, and severe adverse events, to the currently used vaccines. No data were available on the efficacy or effectiveness of PNEU-C-15 or PNEU-C-20. Economic evidence and feasibility assessments supported the use of the PNEU-C-20 vaccine. Conclusion: NACI recommends PNEU-C-20 for adults 65 years of age and older, 50-64 years of age and living with factors placing them at higher risk of pneumococcal disease, and 18-49 years of age with immunocompromising conditions, with PNEU-C-15+PNEU-P-23 an alternative.

Integrated surveillance of antimicrobial resistance and antimicrobial use: Evaluation of the status in Canada (2014-2019).

OBJECTIVE: Integrated surveillance of antimicrobial resistance (AMR) and antimicrobial use (AMU) across One Health sectors is critically important for effective, evidence-based policy, stewardship, and control of AMR. Our objective was to evaluate progress towards achieving comprehensive, integrated AMR/AMU surveillance in Canada. MATERIALS AND METHODS: Based on an environmental scan, interviews of subject matter experts, and reports from the 2014 National Collaborating Centre for Infectious Diseases and the 2016 Canadian Council of Chief Veterinary Officers, we identified 8 core surveillance requirements and their specific components; the latter were assessed using a 2-way classification matrix, with 7 common elements ranked according to development stage. RESULTS: Components that mapped to requirements of a comprehensive, fully integrated AMR/AMU surveillance system were mostly in the lowest stages of development (Exploration or Program Adoption). However, both the establishment of the Canadian AMR Surveillance System integrated reporting and expansion of existing components under the Canadian Nosocomial Infection Surveillance Program and the Canadian Integrated Program for AMR Surveillance are improvements. Regardless, obvious gaps in Canadian AMR/AMU surveillance prevent this from being a comprehensive and integrated One Health program. CONCLUSION: Action is needed in 3 crucial areas: i) development of a complete, integrated AMR/AMU surveillance program, based on current success; ii) changes in Federal/Provincial/Territorial policies to require standardized AMR/AMU reporting; and iii) more resources for AMR/AMU surveillance (dedicated persons, funding, and enabling structures and policy). There is an urgent need for prioritization by Federal/Provincial/Territorial governments to address governance, leadership, and funding to create surveillance systems that inform stewardship and policy.

RéSUMé: OBJECTIF: La surveillance intégrée de la résistance aux antimicrobiens (RAM) et de l'utilisation des antimicrobiens (UAM) dans les secteurs Une seule santé est d'une importance cruciale pour une politique, une gestion et une maitrise efficaces et fondées sur des preuves de la résistance aux antimicrobiens. Notre objectif était d'évaluer les progrès vers la réalisation d'une surveillance complète et intégrée de la RAM/UAM au Canada. MéTHODES: Sur la base d'une analyse de l'environnement, d'entrevues d'experts en la matière et de rapports du Centre de collaboration nationale des maladies infectieuses de 2014 et du Conseil canadien des chefs vétérinaires de 2016, nous avons identifié huit exigences de surveillance de base et leurs composantes spécifiques; ces derniers ont été évalués à l'aide d'une matrice de classification à deux voies, avec sept éléments communs classés selon le stade de développement. RéSULTATS: Les composants correspondant aux exigences d'un système de surveillance de la RAM/UAM complet et entièrement intégré en étaient pour la plupart aux stades les plus bas de développement (Exploration ou Adoption de programme). Cependant, l'établissement du Système canadien de surveillance de la RAM et l'expansion des éléments existants dans le cadre du Programme canadien de surveillance des infections nosocomiales et du Programme intégré canadien de surveillance de la RAM constituent des améliorations. Quoi qu'il en soit, des lacunes évidentes dans la surveillance canadienne de la RAM/UAM l'empêchent d'être un programme Une seule santé complet et intégré. CONCLUSION: Des actions sont nécessaires dans trois domaines cruciaux : 1) le développement d'un programme de surveillance complet et intégré de la RAM/AMU, basé sur le succès actuel; 2) des changements aux politiques fédérales/provinciales/territoriales pour exiger des rapports normalisés sur la RAM/UAM; et 3) davantage de ressources pour la surveillance de la RAM/UAM (personnes dédiées, financement, structures et politiques habilitantes). Il est urgent que les gouvernements fédéral/provincial/territorial établissent des priorités pour aborder la gouvernance, le leadership et le financement afin de créer des systèmes de surveillance qui éclairent la gouvernance et les politiques.

One Health Evaluation of Antimicrobial Use and Resistance Surveillance: A Novel Tool for Evaluating Integrated, One Health Antimicrobial Resistance and Antimicrobial Use Surveillance Programs.

We describe the development, application and utility of our novel, One Health Evaluation of Antimicrobial Use and Resistance Surveillance (OHE-AMURS) tool that we created to evaluate progress toward integrated, One Health surveillance of antimicrobial resistance (AMR) and antimicrobial use (AMU) as a complex system in Canada. We conducted a qualitative inquiry into the current state of policy and programs for integrated AMR/AMU surveillance using explicit and tacit knowledge. To assess the "messy" state of public health surveillance program development, we synthesized recommendations from previous reports by the National Collaborating Centre for Infectious Diseases and the Canadian Council of Chief Veterinary Officers; conducted an environmental scan to find all federal, provincial, and territorial AMR/AMU surveillance programs in Canada; and conducted semi-structured interviews with Canadian subject matter experts. To integrate evidence from these different sources we adapted two published tools to create a new evaluation matrix, deriving 36 components of the ideal integrated AMR/AMU surveillance system. Our two-way matrix tool allowed us to examine seven common, foundational elements of sustainable programs for each component, and assign a stage of development/sustainability ranking for each component according to the matrix definitions. Our adaptable novel tool allowed for granular and repeatable assessment of the many components of a complex surveillance system. The assessment proved robust and exacting to ensure transparency in our methods and results. The matrix allows flexible assignment of program components based on program principles, and stages can be adapted to evaluate any aspect of an AMR/AMU surveillance or other multi-faceted, multi-jurisdictional system. Future refinement should include an assessment of the scope of surveillance components.

Prevalence of antimicrobial-resistant pathogens in Canadian hospitals: results of the Canadian Ward Surveillance Study (CANWARD 2008).

A total of 5,282 bacterial isolates obtained between 1 January and 31 December 31 2008, inclusive, from patients in 10 hospitals across Canada as part of the Canadian Ward Surveillance Study (CANWARD 2008) underwent susceptibility testing. The 10 most common organisms, representing 78.8% of all clinical specimens, were as follows: Escherichia coli (21.4%), methicillin-susceptible Staphylococcus aureus (MSSA; 13.9%), Streptococcus pneumoniae (10.3%), Pseudomonas aeruginosa (7.1%), Klebsiella pneumoniae (6.0%), coagulase-negative staphylococci/Staphylococcus epidermidis (5.4%), methicillin-resistant S. aureus (MRSA; 5.1%), Haemophilus influenzae (4.1%), Enterococcus spp. (3.3%), Enterobacter cloacae (2.2%). MRSA comprised 27.0% (272/1,007) of all S. aureus isolates (genotypically, 68.8% of MRSA were health care associated [HA-MRSA] and 27.6% were community associated [CA-MRSA]). Extended-spectrum ß-lactamase (ESBL)-producing E. coli occurred in 4.9% of E. coli isolates. The CTX-M type was the predominant ESBL, with CTX-M-15 the most prevalent genotype. MRSA demonstrated no resistance to ceftobiprole, daptomycin, linezolid, telavancin, tigecycline, or vancomycin (0.4% intermediate intermediate resistance). E. coli demonstrated no resistance to ertapenem, meropenem, or tigecycline. Resistance rates with P. aeruginosa were as follows: colistin (polymyxin E), 0.8%; amikacin, 3.5%; cefepime, 7.2%; gentamicin, 12.3%; fluoroquinolones, 19.0 to 24.1%; meropenem, 5.6%; piperacillin-tazobactam, 8.0%. A multidrug-resistant (MDR) phenotype occurred frequently in P. aeruginosa (5.9%) but uncommonly in E. coli (1.2%) and K. pneumoniae (0.9%). In conclusion, E. coli, S. aureus (MSSA and MRSA), P. aeruginosa, S. pneumoniae, K. pneumoniae, H. influenzae, and Enterococcus spp. are the most common isolates recovered from clinical specimens in Canadian hospitals. The prevalence of MRSA was 27.0% (of which genotypically 27.6% were CA-MRSA), while ESBL-producing E. coli occurred in 4.9% of isolates. An MDR phenotype was common in P. aeruginosa.

Layperson-Led vs Professional-Led Behavioral Interventions for Weight Loss in Pediatric Obesity: A Systematic Review and Meta-analysis.

Importance: The appropriate approach for weight loss among children and adolescents with overweight and obesity remains unclear. Objective: To evaluate the difference in the treatment outcomes associated with behavioral weight loss interventions led by laypersons and professionals in comparison with unsupervised control arms among children and adolescents with overweight and obesity. Data Sources: For this systematic review and meta-analysis, the Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, the Cochrane Library, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases were searched from January 1, 1996, to June 1, 2019. Study Selection: Included in this study were randomized clinical trials (RCTs) of behavioral interventions lasting at least 12 weeks for children and adolescents (aged 5-18 years) with overweight and obesity. Exclusion criteria included non-RCT studies, interventions lasting less than 12 weeks, adult enrollment, participants with other medical diagnoses, pharmacological treatment use, and articles not written in English. Two of 6 reviewers independently screened all citations. Of 25 586 citations, after duplicate removal, 78 RCTs (5780 participants) met eligibility criteria. Data Extraction and Synthesis: A bayesian framework and Markov chain Monte Carlo simulation methods were used to combine direct and indirect associations. Random-effects and fixed-effect network meta-analysis models were used with the preferred model chosen by comparing the deviance information criteria. This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The immediate and sustained changes in weight and body mass index (BMI) standardized mean difference (SMD) were primary outcomes planned before data collection began, whereas waist circumference and percent body fat were secondary outcomes. The hypothesis being tested was formulated before the data collection. Results: Of 25 586 citations retrieved, we included 78 RCTs (5780 participants), with a follow-up of 12 to 104 weeks. Compared with the control condition, random-effects models revealed that professional-led weight loss interventions were associated with reductions in weight (mean difference [MD], -1.60 kg [95% CI, -2.30 to -0.99 kg]; 68 trials; P < .001) and BMI (SMD, -0.30 [95% CI, -0.39 to -0.20]; 59 trials; P < .001) that were not sustained long term (weight MD, -1.02 kg [95% CI, -2.20 to 0.34 kg]; 21 trials; P = .06; BMI SMD, -0.12 [95% CI, -0.46 to 0.21]; 20 trials; P < .001). There was no association between layperson-led interventions and weight loss in the short-term (MD, -1.40 kg [95% CI, -3.00 to 0.26 kg]; 5 trials; P = .05) or long-term (MD, -0.98 kg [95% CI, -3.60 to 1.80 kg]; 1 trial; P = .23) compared with standard care. No difference was found in head-to-head trials (professional vs layperson MD, -0.25 kg [95% CI -1.90 to 1.30 kg]; 5 trials; P = .38). Conclusions and Relevance: This systematic review and meta-analysis found that professional-led weight loss interventions were associated with short-term but not sustained weight reduction among children and adolescents with overweight or obesity, and the evidence for layperson-led approaches was insufficient to draw firm conclusions.

Antimicrobial susceptibility of 3931 organisms isolated from intensive care units in Canada: Canadian National Intensive Care Unit Study, 2005/2006.

We tested the in vitro activity of 15 antimicrobials against Gram-positive cocci and 12 antimicrobials against Gram-negative bacilli versus 3931 isolates (20 most common organisms) obtained between September 1, 2005, and June 30, 2006, from 19 intensive care units (ICUs) across Canada. The most active (based upon MIC only) agents against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis were dalbavancin, daptomycin, linezolid, tigecycline, and vancomycin with MIC(90) (microg/mL) of 0.06 and < or =0.03, 0.25 and 0.12, 2 and 1, 0.5 and 0.5, and 1 and 2, respectively. The most active agents against vancomycin-resistant enterococci were daptomycin, linezolid, and tigecycline with MIC(90) (microg/mL) of 1, 4, and 0.12, respectively. The most active agents against Escherichia coli were amikacin, cefepime, meropenem, piperacillin/tazobactam, and tigecycline with MIC(90) (microg/mL) of 4, < or =1, < or =0.12, 8, and 0.5, respectively. The most active agents against extended-spectrum beta-lactamase-producing E. coli were meropenem and tigecycline with MIC(90) (microg/mL) of < or =0.12 and 1, respectively. The most active agents against Pseudomonas aeruginosa were amikacin, cefepime, meropenem, and piperacillin/tazobactam with MIC(90) (microg/mL) of 16, 32, 16, and 64, respectively. The most active agents against Stenotrophomonas maltophilia were tigecycline and trimethoprim/sulfamethoxazole with MIC(90) (microg/mL) of 4 and 4, respectively. The most active agents against Acinetobacter baumannii were fluoroquinolones (e.g., levofloxacin), meropenem, and tigecycline with MIC(90) (microg/mL) of 0.5, 1, and 2, respectively. In conclusion, the most active agents versus Gram-positive cocci and Gram-negative bacilli obtained from Canadian ICUs were daptomycin, linezolid, tigecycline, dalbavancin and amikacin, cefepime, meropenem, piperacillin/tazobactam, and tigecycline (not P. aeruginosa), respectively.

Return on investment in healthcare leadership development programs.

Purpose Strong leadership has been shown to foster change, including loyalty, improved performance and decreased error rates, but there is a dearth of evidence on effectiveness of leadership development programs. To ensure a return on the huge investments made, evidence-based approaches are needed to assess the impact of leadership on health-care establishments. As a part of a pan-Canadian initiative to design an effective evaluative instrument, the purpose of this paper was to identify and summarize evidence on health-care outcomes/return on investment (ROI) indicators and metrics associated with leadership quality, leadership development programs and existing evaluative instruments. Design/methodology/approach The authors performed a scoping review using the Arksey and O'Malley framework, searching eight databases from 2006 through June 2016. Findings Of 11,868 citations screened, the authors included 223 studies reporting on health-care outcomes/ROI indicators and metrics associated with leadership quality (73 studies), leadership development programs (138 studies) and existing evaluative instruments (12 studies). The extracted ROI indicators and metrics have been summarized in detail. Originality/value This review provides a snapshot in time of the current evidence on ROI indicators and metrics associated with leadership. Summarized ROI indicators and metrics can be used to design an effective evaluative instrument to assess the impact of leadership on health-care organizations.

Long-term trends in invasive pneumococcal disease in Manitoba, Canada.

Invasive pneumococcal disease (IPD) remains a significant public health problem in Manitoba, Canada although publically-funded pneumococcal conjugate (PCV7 and PCV13) and polysaccharide (PPV23) vaccination programs exist. We analyzed routine surveillance and administrative health data to examine trends in IPD rates as these vaccines were introduced. Data on all individuals with a laboratory-confirmed diagnosis of IPD between 2001 and 2014 were obtained from the provincial Communicable Diseases Surveillance database and linked with Manitoba's provincial immunization registry and physician and hospital databases. We calculated IPD incidence rates overall, by serotype and for different population subgroups defined by socio-demographic and clinical (e.g., chronic diseases, immune status) characteristics. Annual IPD incidence (95%CI) was 8.6 (8.2-9.1)/100,000 people during the study period (n = 1092), and rates were higher in recent years and in regions with predominately indigenous populations. Reduction in the incidence of serotypes included in PCV7 have been offset by rising rates of PCV13-only serotypes in children, and more recently by rising rates of PPV-only serotypes and non-vaccine serotypes among young children and older adults (≥ 65 years). Rates were 3 times higher in those with a chronic disease and highest (> 175-fold) among alcoholics, organ-transplant, and chronic kidney failure patients. The case fatality rate was 12.0% within 30 d of diagnosis. Despite the introduction of several vaccination programs, overall rates of IPD have not declined in Manitoba in the last decade, due to increase in incidence of non-PCV7 serotypes. A disproportionately high burden of disease impacts indigenous communities and people with chronic disease.

Molecular characterisation of Canadian paediatric multidrug-resistant Streptococcus pneumoniae from 1998-2004.

Multidrug-resistant (MDR) Streptococcus pneumoniae (i.e. resistant to three different antimicrobial classes) is a global concern. The molecular epidemiology of MDR S. pneumoniae has not been characterised in Canadian paediatric isolates. Paediatric MDR S. pneumoniae were obtained from a national surveillance study. Susceptibility testing was performed by the methods of the Clinical and Laboratory Standards Institute. Phenotypic and genotypic relatedness were assessed by serotyping and pulsed-field gel electrophoresis (PFGE). Penicillin resistance was assessed with polymerase chain reaction (PCR) followed by DNA sequencing of penicillin-binding proteins (PBPs) 1A, 2B and 2X. Macrolide resistance was assessed by PCR-based detection of mef(E) and erm(B). PCR and sequencing of the dihydrofolate reductase (DHFR) gene was performed to assess resistance to trimethoprim/sulphamethoxazole (T/S). Seventy (98.6%) of 71 MDR paediatric isolates were concomitantly resistant to penicillin, erythromycin and T/S. Resistance genes mef(E) (66.2%) or erm(B) (22.5%) or both mef(E) and erm(B) (8.5%) were associated with macrolide resistance, and the prevalence of erm(B) increased significantly (P=0.0001) over time. Penicillin resistance was associated with amino acid substitutions in PBPs 1A, 2B and 2X. Resistance to T/S was associated with amino acid substitutions in the DHFR gene; in particular, Ile100-->Leu was detected in all isolates analysed. PFGE revealed three clusters of isolates that were genetically related and associated with specific serotypes (Taiwan(19F), Spain(23F), Spain(14) and France(9V)), suggesting clonal expansion as the primary means of paediatric MDR S. pneumoniae dissemination in Canada. The heptavalent pneumococcal vaccine Prevnar, currently approved in Canada for use in children < or =2 years of age, provided excellent coverage (90.2%) of paediatric MDR S. pneumoniae. In conclusion, paediatric MDR S. pneumoniae simultaneously resistant to penicillin, erythromycin and T/S are genetically similar and disseminating across Canada. Prevnar provides excellent coverage of paediatric MDR S. pneumoniae.

The ketolides: a critical review.

Ketolides are a new class of macrolides designed particularly to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A, and retain the erythromycin macrolactone ring structure as well as the D-desosamine sugar attached at position 5. The defining characteristic of the ketolides is the removal of the neutral sugar, L-cladinose from the 3 position of the ring and the subsequent oxidation of the 3-hydroxyl to a 3-keto functional group. The ketolides presently under development additionally contain an 11, 12 cyclic carbamate linkage in place of the two hydroxyl groups of erythromycin A and an arylalkyl or an arylallyl chain, imparting in vitro activity equal to or better than the newer macrolides. Telithromycin is the first member of this new class to be approved for clinical use, while ABT-773 is presently in phase III of development. Ketolides have a mechanism of action very similar to erythromycin A from which they have been derived. They potently inhibit protein synthesis by interacting close to the peptidyl transferase site of the bacterial 50S ribosomal subunit. Ketolides bind to ribosomes with higher affinity than macrolides. The ketolides exhibit good activity against Gram-positive aerobes and some Gram-negative aerobes, and have excellent activity against drug-resistant Streptococcus pneumoniae, including macrolide-resistant (mefA and ermB strains of S. pneumoniae). Ketolides such as telithromycin display excellent pharmacokinetics allowing once daily dose administration and extensive tissue distribution relative to serum. Evidence suggests the ketolides are primarily metabolised in the liver and that elimination is by a combination of biliary, hepatic and urinary excretion. Pharmacodynamically, ketolides display an element of concentration dependent killing unlike macrolides which are considered time dependent killers. Clinical trial data are only available for telithromycin and have focused on respiratory infections including community-acquired pneumonia, acute exacerbations of chronic bronchitis, sinusitis and streptococcal pharyngitis. Bacteriological and clinical cure rates have been similar to comparators. Limited data suggest very good eradication of macrolide-resistant and penicillin-resistant S. pneumoniae. As a class, the macrolides are well tolerated and can be used safely. Limited clinical trial data suggest that ketolides have similar safety profiles to the newer macrolides. Telithromycin interacts with the cytochrome P450 enzyme system (specifically CYP 3A4) in a reversible fashion and limited clinically significant drug interactions occur. In summary, clinical trials support the clinical efficacy of the ketolides in upper and lower respiratory tract infections caused by typical and atypical pathogens including strains resistant to penicillins and macrolides. Considerations such as local epidemiology, patterns of resistance and ketolide adverse effects, drug interactions and cost relative to existing agents will define the role of these agents. The addition of the ketolides in the era of antibacterial resistance provides clinicians with more options in the treatment of respiratory infections.

A review of clinical failures associated with macrolide-resistant Streptococcus pneumoniae.

The emerging reports of clinical failures using macrolides and their associations with macrolide-resistant Streptococcus pneumoniae prompted us to review the literature describing these cases. Thirty-three cases reporting macrolide treatment failure during treatment of pneumococcal infections were available for review. The most prevalent diagnosis (24/27 or 88.8% of available diagnoses) was community-acquired pneumonia (CAP). Previous medical history included cardiopulmonary disease in eight (24.2%) and immunocompromised states in five (15.1%) patients. The majority, 31/33 (93.9%) of patients received oral macrolide treatment in an outpatient setting. S. pneumoniae was isolated from the blood in 26 (78.8%) of 33 patients, three (9.1%) patients had bacteria present in both blood and cerebrospinal fluid, two (6%) patients grew S. pneumoniae from blood and bronchial washings and two (6%) patients had positive sputum cultures. The MLS(B) phenotype was the most predominant phenotype present in 12 (63.2%) of 19 patients. After failing initial macrolide treatment, 26 (78.8%) of 33 patients received parenteral antibiotic treatment. Of 33 patients admitted to hospital, 29 (87.8%) had their outcome described as 'survived'.

Antimicrobial susceptibility of 15,644 pathogens from Canadian hospitals: results of the CANWARD 2007-2009 study.

The CANWARD study (Canadian Ward Surveillance Study) assessed the antimicrobial susceptibility of a variety of available agents against 15 644 pathogens isolated from patients in Canadian hospitals between 2007 and 2009. The most active (based on MIC data) agents against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci were daptomycin, linezolid, tigecycline, and vancomycin (MRSA only) with MIC(90)'s (µg/mL) of 0.25 and 2, 2 and 2, 0.5 and 0.12, and 1, respectively. The most active agents against extended-spectrum ß-lactamase-producing Escherichia coli were colistin (polymyxin E), doripenem, ertapenem, meropenem, and tigecycline with MIC(90)'s (µg/mL) of 1, ≤ 0.12, 0.25, ≤ 0.12, and 1, respectively. The most active agents against Pseudomonas aeruginosa were amikacin, cefepime, ceftazidime, colistin, doripenem, meropenem, and piperacillin-tazobactam with MIC(90)'s (µg/mL) of 32, 16, 32, 2, 4, 8, and 64, respectively. Overall, the most active agents versus Gram-positive cocci from Canadian hospitals were vancomycin, linezolid, daptomycin, and tigecycline and versus Gram-negative bacilli were amikacin, cefepime, doripenem, ertapenem (excluding Pseudomonas aeruginosa), meropenem, piperacillin-tazobactam, and tigecycline (excluding Pseudomonas aeruginosa).

Antimicrobial-resistant pathogens in intensive care units in Canada: results of the Canadian National Intensive Care Unit (CAN-ICU) study, 2005-2006.

Between 1 September 2005 and 30 June 2006, 19 medical centers collected 4,180 isolates recovered from clinical specimens from patients in intensive care units (ICUs) in Canada. The 4,180 isolates were collected from 2,292 respiratory specimens (54.8%), 738 blood specimens (17.7%), 581 wound/tissue specimens (13.9%), and 569 urinary specimens (13.6%). The 10 most common organisms isolated from 79.5% of all clinical specimens were methicillin-susceptible Staphylococcus aureus (MSSA) (16.4%), Escherichia coli (12.8%), Pseudomonas aeruginosa (10.0%), Haemophilus influenzae (7.9%), coagulase-negative staphylococci/Staphylococcus epidermidis (6.5%), Enterococcus spp. (6.1%), Streptococcus pneumoniae (5.8%), Klebsiella pneumoniae (5.8%), methicillin-resistant Staphylococcus aureus (MRSA) (4.7%), and Enterobacter cloacae (3.9%). MRSA made up 22.3% (197/884) of all S. aureus isolates (90.9% of MRSA were health care-associated MRSA, and 9.1% were community-associated MRSA), while vancomycin-resistant enterococci (VRE) made up 6.7% (11/255) of all enterococcal isolates (88.2% of VRE had the vanA genotype). Extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae occurred in 3.5% (19/536) and 1.8% (4/224) of isolates, respectively. All 19 ESBL-producing E. coli isolates were PCR positive for CTX-M, with bla CTX-M-15 occurring in 74% (14/19) of isolates. For MRSA, no resistance against daptomycin, linezolid, tigecycline, and vancomycin was observed, while the resistance rates to other agents were as follows: clarithromycin, 89.9%; clindamycin, 76.1%; fluoroquinolones, 90.1 to 91.8%; and trimethoprim-sulfamethoxazole, 11.7%. For E. coli, no resistance to amikacin, meropenem, and tigecycline was observed, while resistance rates to other agents were as follows: cefazolin, 20.1%; cefepime, 0.7%; ceftriaxone, 3.7%; gentamicin, 3.0%; fluoroquinolones, 21.1%; piperacillin-tazobactam, 1.9%; and trimethoprim-sulfamethoxazole, 24.8%. Resistance rates for P. aeruginosa were as follows: amikacin, 2.6%; cefepime, 10.2%; gentamicin, 15.2%; fluoroquinolones, 23.8 to 25.5%; meropenem, 13.6%; and piperacillin-tazobactam, 9.3%. A multidrug-resistant (MDR) phenotype (resistance to three or more of the following drugs: cefepime, piperacillin-tazobactam, meropenem, amikacin or gentamicin, and ciprofloxacin) occurred frequently in P. aeruginosa (12.6%) but uncommonly in E. coli (0.2%), E. cloacae (0.6%), or K. pneumoniae (0%). In conclusion, S. aureus (MSSA and MRSA), E. coli, P. aeruginosa, H. influenzae, Enterococcus spp., S. pneumoniae, and K. pneumoniae are the most common isolates recovered from clinical specimens in Canadian ICUs. A MDR phenotype is common for P. aeruginosa isolates in Canadian ICUs.

Telithromycin in the treatment of acute bacterial sinusitis, acute exacerbations of chronic bronchitis, and community-acquired pneumonia.

Acute bacterial sinusitis (ABS), acute exacerbations of chronic bronchitis (AECB), and community-acquired pneumonia (CAP) are common conditions and constitute a substantial socioeconomic burden. The ketolides are a new class of antibacterials with a targeted spectrum of antibacterial activity. In vitro, telithromycin is active against common bacterial pathogens that cause upper and lower respiratory tract infections, including some isolates that are resistant to other antibiotic classes. In 2004, telithromycin was the first ketolide antibiotic approved for clinical use by the US Food and Drug Administration for the treatment of adult outpatients with ABS, AECB, and mild-to-moderate CAP. This review discusses the use of telithromycin in the treatment of these infections, providing an overview of its antibacterial activity, pharmacokinetic and pharmacodynamic properties, clinical efficacy, and tolerability-safety, and concludes that telithromycin is an appropriate option for the treatment of community-acquired ABS, AECB, and mild-to-moderate CAP.

The use of macrolides in treatment of upper respiratory tract infections.

Antimicrobial resistance is a growing problem among upper respiratory tract pathogens. Resistance to beta-lactam drugs among Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes is increasing. As safe and well-tolerated antibiotics, macrolides play a key role in the treatment of community-acquired upper respiratory tract infections (RTIs). Their broad spectrum of activity against gram-positive cocci, such as S. pneumoniae and S. pyogenes, atypical pathogens, H. influenzae (azithromycin and clarithromycin), and Moraxella catarrhalis, has led to the widespread use of macrolides for empiric treatment of upper RTIs and as alternatives for patients allergic to beta-lactams. Macrolide resistance is increasing among pneumococci and recently among S. pyogenes, and is associated with increasing use of the newer macrolides, such as azithromycin. Ribosomal target modification mediated by erm(A) and erm(B) genes and active efflux due to mef(A) and mef(E) are the principal mechanisms of resistance in both S. pneumoniae and S. pyogenes. Recently, ribosomal protein and RNA mutations have been found to be responsible for acquired resistance to macrolides in S. pneumoniae, S. pyogenes, and H. influenzae. Although macrolides are only weakly active against macrolide-resistant streptococci species, producing an efflux pump (mef), and are inactive against pathogens with ribosomal target modification (erm), treatment failures are uncommon. Therefore, macrolide therapy, for now, remains a good alternative for treatment of upper RTIs; however, continuous monitoring of the local resistance patterns is essential.

Expression of the mef(E) gene encoding the macrolide efflux pump protein increases in Streptococcus pneumoniae with increasing resistance to macrolides.

Active macrolide efflux is a major mechanism of macrolide resistance in Streptococcus pneumoniae in many parts of the world, especially North America. In Canada, this active macrolide efflux in S. pneumoniae is predominantly due to acquisition of the mef(E) gene. In the present study, we assessed the mef(E) gene sequence as well as mef(E) expression in variety of low- and high-level macrolide-resistant, clindamycin-susceptible (M-phenotype) S. pneumoniae isolates (erythromycin MICs, 1 to 32 microg/ml; clindamycin MICs, < or = 0.25 microg/ml). Southern blot hybridization with mef(E) probe and EcoRI digestion and relative real-time reverse transcription-PCR were performed to study the mef(E) gene copy number and expression. Induction of mef(E) expression was analyzed by Etest susceptibility testing pre- and postincubation with subinhibitory concentrations of erythromycin, clarithromycin, azithromycin, telithromycin, and clindamycin. The macrolide efflux gene, mef(E), was shown to be a single-copy gene in all 23 clinical S. pneumoniae isolates tested, and expression post-macrolide induction increased 4-, 6-, 20-, and 200-fold in isolates with increasing macrolide resistance (erythromycin MICs 2, 4, 8, and 32 microg/ml, respectively). Sequencing analysis of the macrolide efflux genetic assembly (mega) revealed that mef(E) had a 16-bp deletion 153 bp upstream of the putative start codon in all 23 isolates. A 119-bp intergenic region between mef(E) and mel was sequenced, and a 99-bp deletion was found in 11 of the 23 M-phenotype S. pneumoniae isolates compared to the published mega sequence. However, the mef(E) gene was fully conserved among both high- and low-level macrolide-resistant isolates. In conclusion, increased expression of mef(E) is associated with higher levels of macrolide resistance in macrolide-resistant S. pneumoniae.