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1.  Trends in antiviral therapy of adults hospitalized with influenza in Canada since the end of the 2009 pandemic 
Background
Multiple observational studies have associated antiviral treatment of patients hospitalized with influenza with improved outcome, including reduced mortality. During the 2009–2010 H1N1 pandemic increased use of antiviral treatment of hospital patients was reported. We have carried out prospective surveillance for influenza in patients in a large network of Canadian hospitals since 2006. We wished to assess trends in antiviral use in the two seasons (2010–2011 and 2011–2012) since the end of the pandemic.
Findings
Adults (>16 years) testing positive for influenza at the time of or during admission to participating Canadian hospitals were prospectively reviewed. In 2009–2010 there were 1132 confirmed cases, 1107 in 2010–2011 and 631 in 2011–2012. Information on antiviral therapy was available in >95% in each year. Rising to 89.6% in 2009, the proportion of adult patients treated with antiviral therapy fell to 79.9% and 65.7% in the two subsequent seasons (p < 0.001). Oseltamivir was the antiviral agent used in >98% of cases in each year. The median time from onset of symptoms to initiation of antiviral therapy was three days. The treatment proportion fell across all age groups, co-morbid conditions and disease severity.
Conclusion
Despite evidence for benefit of antiviral therapy, and clinical practice guidelines recommending treatment of this population, antiviral therapy of Canadian adults hospitalized with influenza has progressively fallen in the two seasons since the end of the 2009–2010 influenza pandemic.
doi:10.1186/2047-2994-3-2
PMCID: PMC3895698  PMID: 24405855
2.  Proteomic Analysis of a NAP1 Clostridium difficile Clinical Isolate Resistant to Metronidazole 
PLoS ONE  2014;9(1):e82622.
Background
Clostridium difficile is an anaerobic, Gram-positive bacterium that has been implicated as the leading cause of antibiotic-associated diarrhea. Metronidazole is currently the first-line treatment for mild to moderate C. difficile infections. Our laboratory isolated a strain of C. difficile with a stable resistance phenotype to metronidazole. A shotgun proteomics approach was used to compare differences in the proteomes of metronidazole-resistant and -susceptible isolates.
Methodology/Principal Findings
NAP1 C. difficile strains CD26A54_R (Met-resistant), CD26A54_S (reduced- susceptibility), and VLOO13 (Met-susceptible) were grown to mid-log phase, and spiked with metronidazole at concentrations 2 doubling dilutions below the MIC. Peptides from each sample were labeled with iTRAQ and subjected to 2D-LC-MS/MS analysis. In the absence of metronidazole, higher expression was observed of some proteins in C. difficile strains CD26A54_S and CD26A54_R that may be involved with reduced susceptibility or resistance to metronidazole, including DNA repair proteins, putative nitroreductases, and the ferric uptake regulator (Fur). After treatment with metronidazole, moderate increases were seen in the expression of stress-related proteins in all strains. A moderate increase was also observed in the expression of the DNA repair protein RecA in CD26A54_R.
Conclusions/Significance
This study provided an in-depth proteomic analysis of a stable, metronidazole-resistant C. difficile isolate. The results suggested that a multi-factorial response may be associated with high level metronidazole-resistance in C. difficile, including the possible roles of altered iron metabolism and/or DNA repair.
doi:10.1371/journal.pone.0082622
PMCID: PMC3882210  PMID: 24400070
3.  Characterization of a Stable, Metronidazole-Resistant Clostridium difficile Clinical Isolate 
PLoS ONE  2013;8(1):e53757.
Background
Clostridium difficile are Gram-positive, spore forming anaerobic bacteria that are the leading cause of healthcare-associated diarrhea, usually associated with antibiotic usage. Metronidazole is currently the first-line treatment for mild to moderate C. difficile diarrhea however recurrence occurs at rates of 15–35%. There are few reports of C. difficile metronidazole resistance in the literature, and when observed, the phenotype has been transient and lost after storage or exposure of the bacteria to freeze/thaw cycles. Owing to the unstable nature of the resistance phenotype in the laboratory, clinical significance and understanding of the resistance mechanisms is lacking.
Methodology/Principal Findings
Genotypic and phenotypic characterization was performed on a metronidazole resistant clinical isolate of C. difficile. Whole-genome sequencing was used to identify potential genetic contributions to the phenotypic variation observed with molecular and bacteriological techniques. Phenotypic observations of the metronidazole resistant strain revealed aberrant growth in broth and elongated cell morphology relative to a metronidazole-susceptible, wild type NAP1 strain. Comparative genomic analysis revealed single nucleotide polymorphism (SNP) level variation within genes affecting core metabolic pathways such as electron transport, iron utilization and energy production.
Conclusions/Significance
This is the first characterization of stable, metronidazole resistance in a C. difficile isolate. The study provides an in-depth genomic and phenotypic analysis of this strain and provides a foundation for future studies to elucidate mechanisms conferring metronidazole resistance in C. difficile that have not been previously described.
doi:10.1371/journal.pone.0053757
PMCID: PMC3547915  PMID: 23349739
4.  Antimicrobial Susceptibilities of Health Care-Associated and Community-Associated Strains of Methicillin-Resistant Staphylococcus aureus from Hospitalized Patients in Canada, 1995 to 2008▿  
We determined the in vitro antimicrobial susceptibilities of 7,942 methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained from patients hospitalized in 48 Canadian hospitals from 1995 to 2008. Regional variations in susceptibilities were identified. The dissemination of community-associated strains in Canada appears to have contributed to increased susceptibility of MRSA to several non-β-lactam antimicrobial agents in the past decade. Reduced susceptibility to glycopeptides was not identified.
doi:10.1128/AAC.01717-09
PMCID: PMC2863599  PMID: 20231402
5.  Risk factors for and outcomes associated with clinical isolates of Escherichia coli and Klebsiella species resistant to extended-spectrum cephalosporins among patients admitted to Canadian hospitals 
BACKGROUND:
Clinical features associated with Gram-negative bacterial isolates with extended-spectrum beta-lactamase (ESBL)- and AmpC-mediated resistance identified in Canadian hospitals is largely unknown. The objective of the present study was to determine the demographics, risk factors and outcomes of patients with ESBL- or AmpC-mediated resistant organisms in Canadian hospitals.
METHODS:
Patients with clinical cultures of Escherichia coli or Klebsiella species were matched with patients with a similar organism but susceptible to third-generation cephalosporins. Molecular identification of the AmpC or ESBL was determined using a combination of polymerase chain reaction and sequence analysis. Univariate and multivariate logistic regression analysis was performed to identify variables associated with becoming a case.
RESULTS:
Eight Canadian hospitals identified 106 cases (ESBL/AmpC) and 106 controls. All risk factors identified in the univariate analysis as a predictor of being an ESBL/AmpC cases at the 0.20 P-value were included in the multivariate analysis. No significant differences in outcomes were observed (unfavourable responses 17% versus 15% and mortality rates 13% versus 7%, P not significant). Multivariate logistic regression found an association of becoming an ESBL/AmpC case with: previous admission to a nursing home (OR 8.28, P=0.01) or acute care facility (OR 1.96, P=0.03), length of stay before infection (OR 3.05, P=0.004), and previous use of first-generation cephalosporins (OR 2.38, P=0.02) or third-generation cephalosporins (OR 4.52, P=0.01). Appropriate antibiotics were more likely to be given to controls (27.0% versus 13.3%, P=0.05) and number of days to appropriate antibiotics was longer for cases (median 2.8 days versus 1.2 days, P=0.05).
CONCLUSION:
The importance of patient medical history, present admission and antibiotic use should be considered for all E coli or Klebsiella species patients pending susceptibility testing results.
PMCID: PMC2770301  PMID: 20808455
AmpC resistance; Case-control; Extended-spectrum beta-lactamases; Outcomes; Risk factors
6.  Detection and Characterization of Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Isolates in Canada: Results from the Canadian Nosocomial Infection Surveillance Program, 1995-2006 ▿ †  
We describe the epidemiology of heterogeneously resistant Staphylococcus aureus (hVISA) identified in Canadian hospitals between 1995 and 2006. hVISA isolates were confirmed by the population analysis profiling-area under the curve method. Only 25 hVISA isolates (1.3% of all isolates) were detected. hVISA isolates were more likely to have been health care associated (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.9 to 14.2) and to have been recovered from patients hospitalized in central Canada (OR, 3.0; 95% CI, 1.2 to 7.4). There has been no evidence of vancomycin “MIC creep” in Canadian strains of methicillin (meticillin)-resistant S. aureus, and hVISA strains are currently uncommon.
doi:10.1128/AAC.01316-09
PMCID: PMC2812162  PMID: 19949062
7.  Risk Factors for SARS Transmission from Patients Requiring Intubation: A Multicentre Investigation in Toronto, Canada 
PLoS ONE  2010;5(5):e10717.
Background
In the 2003 Toronto SARS outbreak, SARS-CoV was transmitted in hospitals despite adherence to infection control procedures. Considerable controversy resulted regarding which procedures and behaviours were associated with the greatest risk of SARS-CoV transmission.
Methods
A retrospective cohort study was conducted to identify risk factors for transmission of SARS-CoV during intubation from laboratory confirmed SARS patients to HCWs involved in their care. All SARS patients requiring intubation during the Toronto outbreak were identified. All HCWs who provided care to intubated SARS patients during treatment or transportation and who entered a patient room or had direct patient contact from 24 hours before to 4 hours after intubation were eligible for this study. Data was collected on patients by chart review and on HCWs by interviewer-administered questionnaire. Generalized estimating equation (GEE) logistic regression models and classification and regression trees (CART) were used to identify risk factors for SARS transmission.
Results
45 laboratory-confirmed intubated SARS patients were identified. Of the 697 HCWs involved in their care, 624 (90%) participated in the study. SARS-CoV was transmitted to 26 HCWs from 7 patients; 21 HCWs were infected by 3 patients. In multivariate GEE logistic regression models, presence in the room during fiberoptic intubation (OR = 2.79, p = .004) or ECG (OR = 3.52, p = .002), unprotected eye contact with secretions (OR = 7.34, p = .001), patient APACHE II score ≥20 (OR = 17.05, p = .009) and patient Pa02/Fi02 ratio ≤59 (OR = 8.65, p = .001) were associated with increased risk of transmission of SARS-CoV. In CART analyses, the four covariates which explained the greatest amount of variation in SARS-CoV transmission were covariates representing individual patients.
Conclusion
Close contact with the airway of severely ill patients and failure of infection control practices to prevent exposure to respiratory secretions were associated with transmission of SARS-CoV. Rates of transmission of SARS-CoV varied widely among patients.
doi:10.1371/journal.pone.0010717
PMCID: PMC2873403  PMID: 20502660
8.  Hypervirulent Clostridium difficile Strains in Hospitalized Patients, Canada1 
Emerging Infectious Diseases  2010;16(4):678-681.
doi:10.3201/eid1604.091152
PMCID: PMC3321949  PMID: 20350386
Clostridium difficile; molecular typing; hypervirulent; community-onset; bacteria; pulsed-field gel electrophoresis; hospitalized patients; Canada; dispatch
9.  Livestock-associated Methicillin-Resistant Staphylococcus aureus Sequence Type 398 in Humans, Canada 
Emerging Infectious Diseases  2010;16(4):587-594.
Recent emergence of infections resulting from this strain is of public health concern.
Rates of colonization with livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) sequence type 398 have been high for pigs and pig farmers in Canada, but prevalence rates for the general human population are unknown. In this study, 5 LA-MRSA isolates, 4 of which were obtained from skin and soft tissue infections, were identified from 3,687 tested MRSA isolates from persons in Manitoba and Saskatchewan, Canada. Further molecular characterization determined that these isolates all contained staphylococcal cassette chromosome (SCC) mecV, were negative for Panton-Valentine leukocidin, and were closely related by macrorestriction analysis with the restriction enzyme Cfr91. The complete DNA sequence of the SCCmec region from the isolate showed a novel subtype of SCCmecV harboring clustered regularly interspaced short palindromic repeats and associated genes. Although prevalence of livestock-associated MRSA seems to be low for the general population in Canada, recent emergence of infections resulting from this strain is of public health concern.
doi:10.3201/eid1604.091435
PMCID: PMC3321955  PMID: 20350371
Methicillin-resistant Staphylococcus aureus; ST398; livestock associated; SCCmec; CRISPR; zoonoses; Canada; bacteria; expedited; research
10.  Mupirocin-Resistant, Methicillin-Resistant Staphylococcus aureus Strains in Canadian Hospitals▿  
Antimicrobial Agents and Chemotherapy  2007;51(11):3880-3886.
Mupirocin resistance in Staphylococcus aureus is increasingly being reported in many parts of the world. This study describes the epidemiology and laboratory characterization of mupirocin-resistant methicillin-resistant S. aureus (MRSA) strains in Canadian hospitals. Broth microdilution susceptibility testing of 4,980 MRSA isolates obtained between 1995 and 2004 from 32 Canadian hospitals was done in accordance with CLSI guidelines. The clinical and epidemiologic characteristics of strains with high-level mupirocin resistance (HLMupr) were compared with those of mupirocin-susceptible (Mups) strains. MRSA strains were characterized by pulsed-field gel electrophoresis (PFGE) and typing of the staphylococcal chromosomal cassette mec. PCR was done to detect the presence of the mupA gene. For strains with mupA, plasmid DNA was extracted and subjected to Southern blot hybridization. A total of 198 (4.0%) HLMupr MRSA isolates were identified. The proportion of MRSA strains with HLMupr increased from 1.6% in the first 5 years of surveillance (1995 to 1999) to 7.0% from 2000 to 2004 (P < 0.001). Patients with HLMupr MRSA strains were more likely to have been aboriginal (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.5 to 9.4; P = 0.006), to have had community-associated MRSA (OR, 2.2; 95% CI, 1.0 to 5.0; P = 0.05), and to have been colonized with MRSA (OR, 1.7; 95% CI, 1.0 to 3.0; P = 0.04). HLMupr MRSA strains were also more likely to be resistant to fusidic acid (21% versus 4% for mupirocin-susceptible strains; P < 0.001). All HLMupr MRSA strains had a plasmid-associated mupA gene, most often associated with a 9-kb HindIII fragment. PFGE typing and analysis of the plasmid profiles indicate that both plasmid transmission and the clonal spread of HLMupr MRSA have occurred in Canadian hospitals. These results indicate that the incidence of HLMupr is increasing among Canadian strains of MRSA and that HLMupr MRSA is recovered from patients with distinct clinical and epidemiologic characteristics compared to the characteristics of patents with Mups MRSA strains.
doi:10.1128/AAC.00846-07
PMCID: PMC2151460  PMID: 17724154
11.  A nosocomial outbreak of community-associated methicillin-resistant Staphylococcus aureus among healthy newborns and postpartum mothers 
BACKGROUND
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has increasingly been isolated from individuals with no predisposing risk factors; however, such strains have rarely been linked to outbreaks in the hospital setting. The present study describes the investigation of an outbreak of CA-MRSA that occurred in the maternal-newborn unit of a large community teaching hospital in Toronto, Ontario.
METHODS
Screening and clinical specimens collected from mothers and newborns delivered during the outbreak period, as well as from staff on the affected unit, were submitted for microbiological testing. Computerized delivery logs and nursing notes were reviewed, and a case control study was conducted.
RESULTS
Analysis by pulsed-field gel electrophoresis revealed 38 babies and seven mothers with MRSA colonization and/or infection by the same unique strain (Canadian MRSA-10-related) from September to December 2004. Isolates were characterized as having the staphylococcal chromosome cassette mec type IVa and were positive for the Panton-Valentine leukocidin gene. No one health care worker was associated with all cases; however, mothers and newborns exposed to one particular nurse (Nurse A) were almost 23 times (odds ratio 22.7, 95% CI 3.3 to 195.9) more likely to acquire MRSA than those with no such contact. MRSA was successfully isolated from Nurse A and from an environmental swab of a telephone recently used by Nurse A; both isolates matched the pulsed-field gel electrophoresis pattern of the outbreak strain.
CONCLUSION
The first nosocomial outbreak of CA-MRSA among healthy newborns and postpartum mothers in Canada is described. Effective control of sustained MRSA transmission within an institution may require prompt identification, treatment and monitoring of colonized and/or infected staff.
PMCID: PMC2533535  PMID: 18923766
Community-acquired MRSA; Panton-Valentine leukocidin; SCCmec type IV
12.  Late Recognition of SARS in Nosocomial Outbreak, Toronto 
Emerging Infectious Diseases  2005;11(2):322-325.
Late recognition of severe acute respiratory syndrome (SARS) was associated with no known SARS contact, hospitalization before the nosocomial outbreak was recognized, symptom onset while hospitalized, wards with SARS clusters, and postoperative status. SARS is difficult to recognize in hospitalized patients with a variety of underlying conditions in the absence of epidemiologic links.
doi:10.3201/eid1102.040607
PMCID: PMC3320463  PMID: 15752456
SARS; nosocomial infections; surveillance; dispatch

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