Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Duration of hospital admission and the need for empirical antipseudomonal therapy.

To reduce selective pressure for antimicrobial resistance, empirical use of antipseudomonal antibiotics is often reserved for patients with late-onset hospital-acquired infections. We examined the likelihood of isolating Pseudomonas aeruginosa as a function of time from hospital admission. We conducted a retrospective cohort study of all positive bacterial cultures in a tertiary-care hospital between March 2010 and November 2011. The primary outcome was the proportion of positive cultures yielding P. aeruginosa. Multivariable logistic regression was employed to assess the impact of time from admission on the likelihood of isolating P. aeruginosa, after adjusting for other important risk factors. A total of 7,668 positive cultures were obtained from 4,108 unique patients during the study interval, including 633 (8.3%) yielding P. aeruginosa. The probability of isolating P. aeruginosa increased linearly from 79/2,044 (3.9%) positive cultures obtained on admission to 153/664 (23%) in the 10th week of admission or beyond. The unadjusted odds ratio was 1.002/day (95% confidence interval [CI], 1.0016 to 1.0028; P < 0.0001); the adjusted odds ratio (aOR) was 1.0007/day (95% CI, 1.0001 to 1.0013; P = 0.02). Other important predictors of P. aeruginosa isolation included respiratory specimen type (aOR, 13.8; 95% CI, 9.1 to 21.1), recent hospital admission (aOR,1.8; 95% CI, 1.4 to 2.3), prior P. aeruginosa isolation during current admission (aOR, 4.9; 95% CI, 3.7 to 6.4), and prior antipseudomonal (aOR, 1.9; 95% CI, 1.4 to 2.5) or nonantipseudomonal (aOR, 1.8; 95% CI, 1.4 to 2.4) antibiotic exposure. It was determined that as time from admission increases, there is a linear increase in the likelihood of P. aeruginosa isolation. Any guidelines which distinguish early from late hospital-acquired infection must consider the implications of time point selection on the likelihood of inadequate P. aeruginosa empirical coverage.

Defining the decision problem: a scoping review of economic evaluations for Clostridioides difficile interventions.

BACKGROUND: Clostridioides difficile infection is the leading cause of healthcare-associated infectious diarrhoea. Several preventative and treatment interventions exist; however, decisions for their use are typically made independent of other interventions along the care pathway. AIM: To assess how the scope of the decision problem is defined in economic evaluations of C. difficile interventions. METHODS: A scoping review was conducted following the Joanna Briggs Institute framework using a comprehensive literature search with C. difficile and economic evaluation as key search concepts. Study selection and extraction were performed independently by two reviewers. An in-depth analysis of all cost-utility and cost-effectiveness analyses was conducted. Care pathway domains (i.e. infection prevention and control, antimicrobial stewardship programmes, prevention, diagnostics, treatment) were defined iteratively, and each study was classified according to the scope of the decision problem: (i) one intervention, one domain; (ii) one intervention, multiple domains; (iii) multiple interventions, one domain; and (iv) multiple interventions, multiple domains. RESULTS: In total, 3886 studies were identified. Of these, 116 studies were included in the descriptive overview, and 46 were included in the in-depth analysis. Most studies limited the scope of the decision problem to one intervention (43/46; 93%). Only three studies (3/46; 7%) assessed multiple interventions - either as bundled vs standalone interventions for prevention (i.e. a single domain), or as sequences of treatments for initial and recurrent infection (i.e. multiple domains). No study assessed multiple interventions across prevention and treatment domains. CONCLUSIONS: Economic evaluations for C. difficile infection assess narrowly defined decision problems which may have implications for optimal healthcare resource allocation.

The predictors and economic burden of early-, mid- and late-onset cardiac implantable electronic device infections: a retrospective cohort study in Ontario, Canada.

The rate of cardiac implantable electronic device (CIED) infection is increasing with time. We sought to determine the predictors, relative mortality, and cost burden of early-, mid- and late-onset CIED infections. We conducted a retrospective cohort study of all CIED implantations in Ontario, Canada between April 2013 and March 2016. The procedures and infections were identified in validated, population-wide health-care databases. Infection onset was categorized as early (0-30 days), mid (31-182 days) and late (183-365 days). Cox proportional hazards regression was used to assess the mortality impact of CIED infections, with infection modelled as a time-varying covariate. A generalized linear model with a log-link and γ distribution was used to compare health-care system costs by infection status. Among 17 584 patients undergoing CIED implantation, 215 (1.2%) developed an infection, including 88 early, 85 mid, and 42 late infections. The adjusted hazard ratio (aHR) of death was higher for patients with early (aHR 2.9, 95% CI 1.7-4.9), mid (aHR 3.3, 95% CI 1.9-5.7) and late (aHR 19.9, 95% CI 9.9-40.2) infections. Total mean 1-year health costs were highest for late-onset (mean Can$113 778), followed by mid-onset (mean Can$85 302), and then early-onset (Can$75 415) infections; costs for uninfected patients were Can$25 631. After accounting for patient and procedure characteristics, there was a significant increase in costs associated with early- (rate ratio (RR) 3.1, 95% CI 2.3-4.1), mid- (RR 2.8, 95% CI 2.4-3.3) and late- (RR 4.7, 95% CI 3.6-6.2) onset infections. In summary, CIED infections carry a tremendous clinical and economic burden, and this burden is disproportionately high for late-onset infections.

Fluoroquinolone use for uncomplicated urinary tract infections in women: a retrospective cohort study.

OBJECTIVES: The United States Food & Drug Administration released an advisory in 2016 that fluoroquinolones be relegated to second-line agents for uncomplicated urinary tract infections (UTIs) given reports of rare but serious side effects; similar warnings have followed from Health Canada and the European Medicines Agency. The objective was to determine whether alternative non-fluoroquinolone agents are as effective as fluoroquinolones in the treatment of UTIs. METHODS: We conducted a retrospective population-based cohort study using administrative health data from six Canadian provinces. We identified women (n = 1 585 997) receiving antibiotic treatment for episodes of uncomplicated UTIs (n = 2 857 243) between January 1 2005 and December 31 2015. Clinical outcomes within 30 days from the initial antibiotic dispensation were compared among patients treated with a fluoroquinolone versus non-fluoroquinolone agents. High-dimensional propensity score adjustments were used to ensure comparable treatment groups and to minimize residual confounding. RESULTS: Fluoroquinolone use for UTI declined over the study period in five of six Canadian provinces and accounted for 22.3-48.5% of treatments overall. The pooled effect across the provinces indicated that fluoroquinolones were associated with fewer return outpatient visits (OR 0.89, 95%CI 0.87-0.92), emergency department visits (OR 0.74, 95%CI 0.61-0.89), hospitalizations (OR 0.83, 95%CI 0.77-0.88), and repeat antibiotic dispensations (OR 0.77, 95%CI 0.75-0.80) within 30 days. CONCLUSIONS: Fluoroquinolones are associated with improved clinical outcomes among women with uncomplicated UTIs. This benefit must be weighed against the risk of fluoroquinolone resistance and rare but serious fluoroquinolone side effects when selecting first-line treatment for these patients.

The association of adequate empirical treatment and time to recovery from bacteraemic urinary tract infections: a retrospective cohort study.

Our objective was to evaluate whether patients with bacteraemic urinary tract infection (UTI) who receive inadequate empirical therapy have worse outcomes than those with adequate therapy. This was a retrospective cohort study of patients with bacteraemic UTI. The exposure variable was adequate versus inadequate empirical antibiotic therapy (AEAT versus IEAT) within 24 h of culture collection. Primary endpoint was time to cure. The primary analysis used propensity score models with inverse probability of treatment weights. A secondary Cox proportional hazards modelling approach was used to test the robustness of this finding, and to evaluate other patient and pathogen predictors of time to cure. Of 469 patients with bacteraemic UTI, 368 (78.5%) received AEAT. There was no significant difference in mortality between those receiving AEAT and those receiving IEAT (adjusted OR 0.86, 95%CI 0.47-1.58). Receipt of AEAT had no association with time to cure (HR 0.93, 95%CI 0.73-1.19, p 0.55) or time to normalization of individual clinical variables. Cox proportional hazards modelling revealed that longer time to cure was associated with liver disease (HR 0.25, 95%CI 0.08-0.76, p 0.015), prior stroke (HR 0.73, 95%CI 0.54-0.99, p 0.044), empirical receipt of piperacillin-tazobactam (HR 0.77, 95%CI 0.59-0.99, p 0.044), qSOFA score >1 (HR 0.68, 95%CI 0.55-0.84, p < 0.001), and hospital-onset UTI (HR 0.53, 95%CI 0.39-0.71, p < 0.001). In conclusion, we found no association between AEAT and time to cure for patients with bacteraemic UTI. It may be appropriate to accept a higher risk threshold when choosing empirical antibiotic regimens, even in centres with high rates of resistant uropathogens.

Decision-support models for empiric antibiotic selection in Gram-negative bloodstream infections.

OBJECTIVES: Early empiric antibiotic therapy in patients can improve clinical outcomes in Gram-negative bacteraemia. However, the widespread prevalence of antibiotic-resistant pathogens compromises our ability to provide adequate therapy while minimizing use of broad antibiotics. We sought to determine whether readily available electronic medical record data could be used to develop predictive models for decision support in Gram-negative bacteraemia. METHODS: We performed a multi-centre cohort study, in Canada and the USA, of hospitalized patients with Gram-negative bloodstream infection from April 2010 to March 2015. We analysed multivariable models for prediction of antibiotic susceptibility at two empiric windows: Gram-stain-guided and pathogen-guided treatment. Decision-support models for empiric antibiotic selection were developed based on three clinical decision thresholds of acceptable adequate coverage (80%, 90% and 95%). RESULTS: A total of 1832 patients with Gram-negative bacteraemia were evaluated. Multivariable models showed good discrimination across countries and at both Gram-stain-guided (12 models, areas under the curve (AUCs) 0.68-0.89, optimism-corrected AUCs 0.63-0.85) and pathogen-guided (12 models, AUCs 0.75-0.98, optimism-corrected AUCs 0.64-0.95) windows. Compared to antibiogram-guided therapy, decision-support models of antibiotic selection incorporating individual patient characteristics and prior culture results have the potential to increase use of narrower-spectrum antibiotics (in up to 78% of patients) while reducing inadequate therapy. CONCLUSIONS: Multivariable models using readily available epidemiologic factors can be used to predict antimicrobial susceptibility in infecting pathogens with reasonable discriminatory ability. Implementation of sequential predictive models for real-time individualized empiric antibiotic decision-making has the potential to both optimize adequate coverage for patients while minimizing overuse of broad-spectrum antibiotics, and therefore requires further prospective evaluation. SUMMARY: Readily available epidemiologic risk factors can be used to predict susceptibility of Gram-negative organisms among patients with bacteraemia, using automated decision-making models.

The second-hand effects of antibiotics: communicating the public health risks of drug resistance.

Antimicrobial resistance (AMR) poses a threat to modern medicine, but there are challenges in communicating its urgency and scope and potential solutions to this growing problem. It is recognized that AMR has a 'language problem' and the way in which healthcare professionals communicate about AMR may not always resonate with patients. Many patients are unaware that antibiotics can have detrimental effects to those beyond the recipient, due to transmission of drug-resistant organisms. The overestimation of benefits and underestimation of risks helps to fuel demand for antibiotic use in situations where they may be of little or no benefit. To better communicate risks, clinicians may borrow the term 'second-hand' from efforts to reduce smoking cessation. We present several examples where antibiotics themselves have second-hand effects beyond the individual recipient in hospitals, long-term care homes and the community. Incorporation of the concept of the second-hand effects of antibiotics into patient counselling, mass messaging and future research may help facilitate a more balanced discussion about the benefits and risks of antibiotic use in order to use these agents more appropriately.

Clinical and echocardiographic predictors of embolism in infective endocarditis: systematic review and meta-analysis.

OBJECTIVES: Prediction of embolic events (EEs) in infective endocarditis (IE) could inform clinical decisions, such as surgical timing. We conducted a systematic review to more precisely define associations between risk factors and EEs. METHODS: We searched two bibliographic databases (1994-2018) for observational studies that reported EEs in IE patients and considered clinical, microbiological or echocardiographic risk factors. Studies that did not use Duke criteria or only investigated a subset of IE patients were excluded. Study quality was assessed using the Newcastle-Ottawa scale. A pooled risk ratio (RR) for each risk factor was estimated using random-effects models; statistical heterogeneity was estimated using I2. RESULTS: Of 3862 unique citations, 47 cohort studies (11 215 IE cases) were included; 54 risk factors were analysed in at least two studies, with nine studies reporting other individual factors. Most studies were of high methodological quality. Major predictors of EEs were intravenous drug use (RR 1.69, 95% CI 1.32-2.17; I2 = 46%), Staphylococcus aureus infection (RR 1.64, 95% CI 1.45-1.86, I2 = 32%), mitral valve vegetation (RR 1.24, 95% CI 1.11-1.37, I2 = 30%), and vegetation size >10 mm (RR 1.87, 95% CI 1.57-2.21, I2 = 48%). EE risk was also higher with human immunodeficiency virus, chronic liver disease, elevated C-reactive protein, Staphylococcus spp. infection, vegetation presence, and multiple, mobile or prosthetic mechanical valve vegetation, and lower with Streptococcus spp. infection. Most findings were unchanged in sensitivity analyses that removed studies with pulmonary EEs from the outcome. CONCLUSIONS: Given the serious consequences of embolism, surgical evaluation may be considered in patients with these risk factors.

Susceptibilities of clinical Clostridium difficile isolates to antimicrobials: a systematic review and meta-analysis of studies since 1970.

OBJECTIVES: Although exposure to antibiotics can cause Clostridium difficile infection, certain antibiotics are used to treat C. difficile. Measurements of antimicrobial C. difficile activity could help to identify antibiotic risk and emergent resistance. Here, we describe publication patterns relating to C. difficile susceptibilities and estimate minimum inhibitory concentrations (MIC) for antibiotic classes in the published literature between January 1970 and June 2014. METHODS: We queried PUBMED and EMBASE for studies reporting antibiotic C. difficile MIC in English or French. We used mixed-effects models to obtain pooled estimates of antibiotic class median MIC (MIC50), 90th percentile of MIC (MIC90), and MIC90:MIC50 ratio. RESULTS: Our search identified 182 articles that met our inclusion criteria, of which 27 were retained for meta-analysis. Aminoglycosides (MIC50 120 mg/L, 95% CI 62-250), 3rd (MIC50 75 mg/L, 95% CI 39-130) and 2nd generation cephalosporins (MIC50 64 mg/L, 95% CI 27-140) had the least C. difficile activity. Rifamycins (MIC50 0.034 mg/L, 95% CI 0.012-0.099) and tetracyclines (MIC50 0.29 mg/L, 95% CI 0.054-1.7) had the highest level of activity. The activity of 3rd generation cephalosporins was more than three times lower than that of 1st generation agents (MIC50 19 mg/L, 95% CI 7.0-54). Time-trends in MIC50 were increasing for carbapenems (70% increase per 10 years) while decreasing for tetracyclines (51% decrease per 10 years). CONCLUSIONS: We found a 3500-fold variation in antibiotic C. difficile MIC50, with aminoglycosides as the least active agents and rifamycins as the most active. Further research is needed to determine how in vitro measures can help assess patient C. difficile risk and guide antimicrobial stewardship.

Utility of prior cultures in predicting antibiotic resistance of bloodstream infections due to Gram-negative pathogens: a multicentre observational cohort study.

OBJECTIVES: Appropriate empiric antibiotic therapy in patients with bloodstream infections due to Gram-negative pathogens can improve outcomes. We evaluated the utility of prior microbiologic results for guiding empiric treatment in Gram-negative bloodstream infections. METHODS: We conducted a multicentre observational cohort study in two large health systems in Canada and the United States, including 1832 hospitalized patients with Gram-negative bloodstream infection (community, hospital and intensive care unit acquired) from April 2010 to March 2015. RESULTS: Among 1832 patients with Gram-negative bloodstream infection, 28% (n = 504) of patients had a documented prior Gram-negative organism from a nonscreening culture within the previous 12 months. A most recent prior Gram-negative organism resistant to a given antibiotic was strongly predictive of the current organism's resistance to the same antibiotic. The overall specificity was 0.92 (95% confidence interval (CI) 0.91-0.93), and positive predictive value was 0.66 (95% CI 0.61-0.70) for predicting antibiotic resistance. Specificities and positive predictive values ranged from 0.77 to 0.98 and 0.43 to 0.78, respectively, across different antibiotics, organisms and patient subgroups. Increasing time between cultures was associated with a decrease in positive predictive value but not specificity. An heuristic based on a prior resistant Gram-negative pathogen could have been applied to one in four patients and in these patients would have changed therapy in one in five. CONCLUSIONS: In patients with a bloodstream infection with a Gram-negative organism, identification of a most recent prior Gram-negative organism resistant to a drug of interest (within the last 12 months) is highly specific for resistance and should preclude use of that antibiotic.

Rationale and development of a business case for antimicrobial stewardship programs in acute care hospital settings.

Background: Antimicrobial stewardship programs (ASPs) have been shown to reduce inappropriate antimicrobial use and its consequences. However, these programs lack legislative requirements in many places and it can be difficult to determine what human resources are required for these programs and how to create a business case to present to hospital administrators for program funding. The objectives of the current paper were to review legislative requirements and outline human resource requirements for ASPs, and to create a base business case for ASPs. Methods: A working group of antimicrobial stewardship experts from across Canada met to discuss the necessary components for creation of a business case for antimicrobial stewardship. A narrative review of the literature of the regulatory requirements and human resource recommendations for ASPs was conducted. Informed by the review and using a consensus decision-making process, the expert working group developed human resource recommendations based on a 1000 bed acute care health care facility in Canada. A spreadsheet based business case model for ASPs was also created. Results: Legislative and /or regulatory requirements for ASPs were found in 2 countries and one state jurisdiction. The literature review and consensus development process recommended the following minimum human resources complement: 1 physician, 3 pharmacists, 0.5 program administrative and coordination support, and 0.4 data analyst support as full time equivalents (FTEs) per 1000 acute care beds. Necessary components for the business case model, including the human resource requirements, were determined to create a spreadsheet based model. Conclusions: There is evidence to support the negative outcomes of inappropriate antimicrobial use as well as the benefits of ASPs. Legislative and /or regulatory requirements for ASPs are not common. The available evidence for human resource recommendations for ASPs using a narrative review process was examined and a base business case modelling scenario was created. As regulatory requirements for ASPs increase, it will be necessary to create accurate business cases for ASPs in order to obtain the necessary funding to render these programs successful.

VAMP2, but not VAMP3/cellubrevin, mediates insulin-dependent incorporation of GLUT4 into the plasma membrane of L6 myoblasts.

Like neuronal synaptic vesicles, intracellular GLUT4-containing vesicles must dock and fuse with the plasma membrane, thereby facilitating insulin-regulated glucose uptake into muscle and fat cells. GLUT4 colocalizes in part with the vesicle SNAREs VAMP2 and VAMP3. In this study, we used a single-cell fluorescence-based assay to compare the functional involvement of VAMP2 and VAMP3 in GLUT4 translocation. Transient transfection of proteolytically active tetanus toxin light chain cleaved both VAMP2 and VAMP3 proteins in L6 myoblasts stably expressing exofacially myc-tagged GLUT4 protein and inhibited insulin-stimulated GLUT4 translocation. Tetanus toxin also caused accumulation of the remaining C-terminal VAMP2 and VAMP3 portions in Golgi elements. This behavior was exclusive to these proteins, because the localization of intracellular myc-tagged GLUT4 protein was not affected by the toxin. Upon cotransfection of tetanus toxin with individual vesicle SNARE constructs, only toxin-resistant VAMP2 rescued the inhibition of insulin-dependent GLUT4 translocation by tetanus toxin. Moreover, insulin caused a cortical actin filament reorganization in which GLUT4 and VAMP2, but not VAMP3, were clustered. We propose that VAMP2 is a resident protein of the insulin-sensitive GLUT4 compartment and that the integrity of this protein is required for GLUT4 vesicle incorporation into the cell surface in response to insulin.

Influence of antibiotics and case exposure on hospital-acquired Clostridium difficile infection independent of illness severity.

BACKGROUND: Previous studies of the association between antibiotic exposure and risk of hospital-acquired Clostridium difficile-associated infection (CDI) have not fully accounted for patient severity of illness, and competing risks. AIM: To determine the potential effects of interventions on hospital-acquired CDI risk. METHODS: All adults admitted to a teaching hospital between 2004 and 2014 for more than two days were included. Exposures to all antibiotics and cases of CDI were determined. Patients were followed until discharge from hospital, death, or acquisition of hospital-acquired CDI (defined as positive toxin assay in unformed stool >2 days following admission). Multivariable proportional hazards competing-risks modelling with time-dependent covariates was used, accounting for patient severity of illness using the Escobar model. FINDINGS: In all, 208,104 patients were studied. Hospital-acquired CDI risk was 0.46 events per 1000 patient-days, decreasing significantly during the study period. Compared to the 5th percentile hospital death risk (0.02%), patients with a 50% risk of death in hospital had an adjusted hazard ratio (aHR) of hospital-acquired CDI of 5.5. Exposure to some antibiotics significantly increased hospital-acquired CDI risk, being highest for carbapenems (aHR: 1.47 after one week of continuous exposure) and intravenous vancomycin (aHR: 1.53). On the ward, sharing a room with other patients newly diagnosed with CDI significantly increased the risk of subsequent disease (aHR: 1.16 on CDI diagnosis day). CONCLUSION: The primary determinant of hospital-acquired CDI was patient severity of illness. Exposure to both antibiotics and other patients with CDI significantly increased the subsequent risk of hospital-acquired CDI but this risk was small relative to patient severity of illness.

Macrolide resistance in bacteremic pneumococcal disease: implications for patient management.

BACKGROUND: Despite pneumococcal antibiotic resistance rates in excess of 25%, macrolides remain first-line agents for the treatment of community-acquired pneumonia. METHODS: Prospective, population-based surveillance was conducted to identify cases of pneumococcal bacteremia in Toronto and Peel, Canada, between 2000 and 2004. "Macrolide failures" were defined as cases of bacteremia occurring during outpatient treatment with macrolide antibiotics or within 2 days after treatment. Macrolide susceptibility was determined according to Clinical Laboratory Standards Institute guidelines; common macrolide resistance mechanisms were determined by genotyping. RESULTS: During the 5 years of surveillance, there were 1696 episodes of pneumococcal bacteremia (8.5 cases/100,000 population/year), of which 60 (3.5%) were failures of outpatient macrolide therapy. Resistant isolates were more common among cases of bacteremia after failure of macrolide therapy (37 [64%] of 58 cases) than among cases of bacteremia after failure of nonmacrolide antibiotics (16 [22%] of 74 cases; P<.001) or cases of bacteremia that occurred without prior antibiotic therapy (193 [12%] of 1569 cases; P<.001). Macrolide failures were significantly more common among cases of pneumococcal bacteremia with isolates exhibiting an erythromycin MIC of 1 microg/mL than among isolates exhibiting MICs < or = 0.25 microg/mL (3 [38%] of 8 cases vs. 21 [1.5%] of 1394 cases of bacteremia; P<.001). Increases in the MIC to 1 microg/mL were not associated with further increases in the likelihood of macrolide failure. Low-level resistance conferred by mefA and high-level resistance conferred by ermB were equally overrepresented among macrolide failures. CONCLUSIONS: Macrolide resistance contributes to an increased risk of macrolide failure, irrespective of the underlying resistance mechanism or of the degree of elevation in erythromycin MIC.

Impact of infection with extended-spectrum ß-lactamase-producing Escherichia coli or Klebsiella species on outcome and hospitalization costs.

BACKGROUND: Extended-spectrum ß-lactamase (ESBL)-producing bacteria are important sources of infection; however, Canadian data evaluating the impact of ESBL-associated infection are lacking. AIM: To determine whether patients infected with ESBL-producing Escherichia coli or Klebsiella species (ESBL-EcKs) exhibit differences in clinical outcome, microbiological outcome, mortality, and/or hospital resource use compared to patients infected with non-ESBL-producing strains. METHODS: A retrospective case-control study of 75 case patients with ESBL-EcKs matched to controls infected with non-ESBL-EcKs who were hospitalized from June 2010 to April 2013 was conducted. Patient-level cost data were provided by the institution's business office. Clinical data were collected using the electronic databases and paper charts. FINDINGS: Median infection-related hospitalization costs per patient were greater for cases than controls (C$10,507 vs C$7,882; median difference: C$3,416; P = 0.04). The primary driver of increased costs was prolonged infection-related hospital length of stay (8 vs 6 days; P = 0.02) with patient location (ward, ICU) and indirect care costs (including costs associated with infection prevention and control) as the leading cost categories. Cases were more likely to experience clinical failure (25% vs 11%; P = 0.03), with a higher all-cause mortality (17% vs 5%; P = 0.04). Less than half of case patients were prescribed appropriate empiric antimicrobial therapy, whereas controls received adequate initial treatment in nearly all circumstances (48% vs 96%; P < 0.01). CONCLUSION: Patients with infection caused by ESBL-EcKs are at increased risk for clinical failure and mortality, with additional cost to the Canadian healthcare system of C$3,416 per patient.

Hospital-acquired invasive group a streptococcal infections in Ontario, Canada, 1992-2000.

BACKGROUND: A significant proportion of invasive group A streptococcal infections are hospital acquired. No large, prospective studies have characterized this subgroup of cases and evaluated the risk of transmission in hospitals. METHODS: We conducted prospective, population-based surveillance of invasive group A streptococcal infections in Ontario, Canada, from 1992 to 2000. Epidemiologic and microbiologic investigations were conducted to identify cross-transmission. RESULTS: We identified 291 hospital-acquired cases (12.4%) among 2351 cases of invasive group A streptococcal disease. Hospital-acquired invasive group A streptococcal infections are heterogeneous, including surgical site (96 cases), postpartum (86 cases), and nonsurgical, nonobstetrical infections (109 cases). Surgical site infections affected 1 of 100,000 surgical procedures and involved all organ systems. Postpartum infections occurred at a rate of 0.7 cases per 10,000 live births and exhibited an excellent prognosis. Nonsurgical, nonobstetrical infections encompassed a broad range of infectious syndromes (case-fatality rate, 37%). Nine percent of cases were associated with in-hospital transmission. Transmission occurred from 3 of 142 patients with community-acquired cases of necrotizing fasciitis requiring intensive care unit (ICU) admission, compared with 1 of 367 patients with community-acquired cases without necrotizing fasciitis admitted to the ICU and 1 of 1551 patients with other cases (P<.001). Fifteen outbreaks were identified; 9 (60%) involved only 2 cases. Hospital staff were infected in 1 of 15 outbreaks, but colonized staff were identified in 6 (60%) of 10 investigations in which staff were screened. CONCLUSIONS: Presentation of hospital-associated invasive group A streptococcal infections is diverse. Cross-transmission is common; illness occurs in patients but rarely in staff. Isolation of new cases of necrotizing fasciitis and intervention after a single nosocomial case may also prevent transmission.

The association of hospital prevention processes and patient risk factors with the risk of Clostridium difficile infection: a population-based cohort study.

BACKGROUND: Clostridium difficile is the most common cause of healthcare-acquired infection; the real-world impacts of some proposed C. difficile prevention processes are unknown. METHODS: We conducted a population-based retrospective cohort study of all patients admitted to acute care hospitals between April 2011 and March 2012 in Ontario, Canada. Hospital prevention practices were determined by survey of infection control programmes; responses were linked to patient-level risk factors and C. difficile outcomes in Ontario administrative databases. Multivariable generalised estimating equation (GEE) regression models were used to assess the impact of selected understudied hospital prevention processes on the patient-level risk of C. difficile infection, accounting for patient risk factors, baseline C. difficile rates and structural hospital characteristics. RESULTS: C. difficile infections complicated 2341 of 653 896 admissions (3.6 per 1000 admissions). Implementation of the selected C. difficile prevention practices was variable across the 159 hospitals with isolation of all patients at onset of diarrhoea reported by 43 (27%), auditing of antibiotic stewardship compliance by 26 (16%), auditing of cleaning practices by 115 (72%), on-site diagnostic testing by 74 (47%), vancomycin as first-line treatment by 24 (15%) and reporting rates to senior leadership by 52 (33%). None of these processes were associated with a significantly reduced risk of C. difficile after adjustment for baseline C. difficile rates, structural hospital characteristics and patient-level factors. Patient-level factors were strongly associated with C. difficile risk, including age, comorbidities, non-elective and medical admissions. CONCLUSIONS: In the largest study to date, selected hospital prevention strategies were not associated with a statistically significant reduction in patients' risk of C. difficile infection. These prevention strategies have either limited effectiveness or were ineffectively implemented during the study period.

Investigating the determinants of decreasing postmyocardial infarction mortality: an analysis of in-hospital data from 1992 and 1997.

BACKGROUND: Although acute myocardial infarction (AMI) is the leading cause of mortality in the industrialized world, postmyocardial infarction mortality rates have been declining in recent decades. Two possible contributing factors toward this encouraging trend include changing patient characteristics and improved patient management. OBJECTIVES: To compare temporal changes in the characteristics and management of patients with AMI at a tertiary care hospital (Sunnybrook and Women's College Health Sciences Centre) in Toronto, Ontario. METHODS: Two hundred hospital charts of patients with AMI as the most responsible diagnosis were reviewed (100 from 1992 and 100 from 1997). One hundred thirty prespecified variables were extracted from each chart, with emphasis placed on baseline clinical characteristics, AMI management and survival. RESULTS: Between 1992 and 1997, AMI in-hospital mortality declined from 20% to 15%. Most baseline clinical characteristics (age, sex, comorbidity, cardiac history, and presenting symptoms and signs) were similar across the 1992 and 1997 patient populations. The only significant risk factor change involved an increase in the prevalence of hypercholesterolemia. In contrast, between 1992 and 1997 there was an increased in-hospital use of anticoagulants, antiplatelets, thrombolytics, beta-blockers, angiotensin-converting enzyme inhibitors and statins. Similarly, there was an increased use of coronary angioplasty and coronary bypass surgery. There was no significant change in the use of AMI therapies that are potentially harmful, including antiarrythmic agents and calcium channel blockers. CONCLUSIONS: AMI patient characteristics were similar between 1992 and 1997 but there were striking changes in AMI treatment patterns. The increased use of evidence-based pharmacotherapy may be the most significant contributing factor to declining postmyocardial infarction mortality.