Successful methodology for large-scale surveillance of severe events following influenza vaccination in Canada, 2011 and 2012.

In 2011 and 2012, a nationwide Canadian vaccine safety surveillance network rapidly collected safety data from healthcare workers (HCW) during the first weeks of the annual influenza vaccination campaign. This network provided the first available post-marketing safety data on seasonal influenza vaccines with information on background rates as a comparator. In 2012, these data were used to investigate a possible safety concern regarding a particular vaccine. An online questionnaire was provided to participating HCW two weeks before the annual influenza vaccination campaign for controls, and eight days after influenza vaccination for vaccinees. Control and vaccinees were requested to report health events occurring in the seven days prior to receiving the questionnaire. Control data were used to calculate background rates. HCW reporting a severe event were followed-up by telephone within 48 hours of the online report to validate the report and check on their health status. More than 22,000 vaccinated HCW were enrolled and surveyed over two seasons and > 90% reported no severe event following vaccination. Validated severe event rates were similar in vaccinated HCW and unvaccinated HCW (2.2% vs 2.3%; p < 0.70). The questionnaire was accurately completed for most reported symptoms, matched the validated report and was able to detect events of interest. Prior to the safety concern, the implicated vaccine was in use at one centre. Reassuring safety data were provided to public health authorities 48 hours after the vaccine was temporarily suspended. Data from this and similar networks can be used for rapid evaluation of vaccine safety and for safety assessment as required by the European Medicines Agency in 2015.

Increased risk of invasive pneumococcal disease in haematological and solid-organ malignancies.

Large-scale population-based studies have reported a significant increase in invasive pneumococcal disease (IPD) in those with underlying haematological or solid-organ malignancy, but limited condition-specific data are available on rates of IPD in the adult population. A retrospective chart review of all patients with IPD (identified prospectively) in the province of Alberta, Canada (population ~3·3 million) was conducted from 2000 to 2004 to study the epidemiology of IPD. Rates of IPD in patients with various haematological and solid-organ malignancies were determined by obtaining the number of these patients at risk from the provincial cancer registry. Compared to the attack rate of IPD in the adult population aged ≥18 years (11·0 cases/100,000 per year, 95% CI 10·44-11·65), there were significantly increased rates of IPD in those with lung cancer (143·6 cases/100,000 per year, OR 13·4, 95% CI 9·3-19·4, P<0·001) and multiple myeloma (673·9 cases/100,000 per year, OR 62·8, 95% CI 39·6-99·8, P<0·001). More modestly increased rates of IPD were found in those with chronic lymphocytic leukaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, and Hodgkin's and non-Hodgkin's lymphoma. There was an increased prevalence of serotype 6A in those with these underlying malignancies, but no other serotypes predominated. Fifty-three percent (48/83) of cases were caused by serotypes in the investigational 13-valent pneumococcal conjugate vaccine (PCV13), and 57/83 (69%) of the cases were caused by serotypes in the 23-valent pneumococcal polysaccharide vaccine (PPV23). The incidence of IPD in adults with certain haematological and solid-organ malignancies is significantly greater than the overall adult population. Such patients should be routinely given pneumococcal polysaccharide vaccine; this population could also be targeted for an expanded valency conjugate vaccine.

Drug-resistant Streptococcus pneumoniae infections: clinical importance, drug treatment, and prevention.

Drug-resistant Streptococcus pneumoniae (DRSP) have complicated the management of pneumococcal infections throughout the world in recent years. Important risk factors for the development of a DRSP infection include recent antibiotic use, young age, immunosuppression, daycare center attendance, and recent hospitalizations. Although intermediate resistance to beta-lactam antibodies does not appear to have an impact on the mortality of S. pneumoniae infections, evidence is accumulating to suggest that more highly resistant isolates may increase mortality. Clinical and bacteriologic failures are more common in DRSP meningitis and otitis media. To select appropriate therapy, one must consider whether a patient has risk factors for resistance, the site and severity of the infection, and antibiotic susceptibility data. Reducing the impact of DRSP may be achieved through reducing antibiotic use in communities and increased understanding of other factors that contribute to the development and transmission of resistance. The most important way to reduce all S. pneumoniae infections is to increase the use of existing polysaccharide vaccines and to begin to use new polysaccharide-protein conjugate vaccines in young children.

Acute infectious conjunctivitis in childhood.

OBJECTIVE: To review the etiology, clinical features and management of acute infectious conjunctivitis in children after the newborn period. DATA SOURCES: Articles obtained from MEDLINE published before March 2000. DATA SELECTION AND EXTRACTION: Representative articles on the etiology and clinical features were selected. Twenty-four clinical trials were also selected. From these articles, the main findings from three placebo controlled trials and two comparative clinical trials involving children are summarized in detail. The main findings from 19 comparative clinical trials in adults are briefly summarized. DATA SYNTHESIS AND CONCLUSIONS: Acute infectious conjunctivitis caused by bacteria or viruses is a very common problem in children after the neonatal period. The most common bacterial pathogens are nontypable Haemophilus influenzae and Streptococcus pneumoniae. Diagnostic microbiology tests are not indicated for uncomplicated cases but may be useful for very young or very ill children if there is no response to initial therapy; for nosocomial cases; for cases suspected to be caused by sexually transmitted pathogens; and for outbreaks. Conjunctivitis is usually a mild, self-limited disease, but topical antibiotics are superior to placebo in reducing the duration and severity of symptoms. Most topical agents have equivalent efficacy; therefore, the selection of first-line agents should include inexpensive drugs with few adverse effects. Good choices include polymyxin/gramicidin, polymyxin/trimethoprim or sulfacetamide. Referral to an ophthalmologist should be considered in situations in which the diagnosis of uncomplicated conjunctivitis is in doubt or if there is no prompt response to therapy.

Beliefs and behaviours of parents regarding antibiotic use by children.

OBJECTIVE: To determine parents' beliefs and behaviours about antibiotic use by their children in the ambulatory setting. DESIGN: Cross-sectional survey, where a self-administered questionnaire was completed by adult caregivers of children before the medical assessment of the child. SETTING: Three paediatric acute care settings (paediatric emergency department [PED], group paediatric practice and after hours walk-in medical clinic). POPULATION STUDIED: Adult caregivers (n=114; 76% mothers, 19% fathers and 4% other caregivers) of children brought for acute care were surveyed. MAIN RESULTS: Forty-one caregivers completed the survey in the PED, 37 in the paediatric office and 36 in the walk-in clinic. They believed that antibiotics were appropriate for ear infections (86%), pharyngitis (77%), bronchitis (49%), sinus colds (20%), cough (12%), colds (8%) and influenza (8%). Sixty-eight per cent of children had received antibiotics in the previous year. Thirteen per cent of caregivers reported previously requesting an antibiotic for their child, 18% believed a previous antibiotic prescription had been unnecessary and 19% had not complied with prescriptions in the past. Concerns about antibiotic use included antibiotic resistance (50%), harm to the immune system (40%), adverse effects (28%) and lack of efficacy (19%). CONCLUSIONS: In this population, parental knowledge and understanding of indications for antibiotics and their adverse effects were good; however, incorrect beliefs and disagreements with physicians did occur. To improve patterns of antibiotic use by children, it will be necessary to understand parents' beliefs, behaviours and information sources better so that misconceptions and disagreements with caregivers can be addressed appropriately.

Disseminated bacille Calmette-Guérin infection in an infant with a novel deletion in the interferon-gamma receptor gene.

Six weeks after receiving BCG vaccination, a Canadian aboriginal infant presented with suspected sepsis, lymphadenopathy and hepatosplenomegaly. Lymph node biopsy revealed macrophages filled with acid-fast bacilli. Mycobacterium bovis was cultured from tissue specimens and there was evidence of concomitant cytomegalovirus disease. The infant died of disseminated BCG infection. A novel deletion at nucleotide 165 in the interferon-gamma receptor (IFN-gammaR1) was identified. The incidence of this mutation in the aboriginal population and the impact on the heterozygous state are unknown.

Bronchodilators for bronchiolitis.

OBJECTIVES: Bronchiolitis is an acute, highly communicable lower respiratory tract infection. Bronchodilators are commonly used in the management of bronchiolitis in North America, but not in the United Kingdom. The objective of this review was to assess the effects of bronchodilators for bronchiolitis. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Reference Update, reference lists of articles, and the files of two of the authors up to June 1998. SELECTION CRITERIA: Randomised trials comparing bronchodilators with placebo in the treatment of bronchiolitis. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Unpublished data were requested from authors when necessary. MAIN RESULTS: In eight trials with 394 children, 46% demonstrated an improved clinical score with bronchodilators compared to 75% with placebo (odds ratio for no improvement 0.29, 95% confidence interval 0.19 to 0.45). However, the inclusion of studies that enrolled people with recurrent wheezes may have biased these results in favour of bronchodilators. Bronchodilator recipients did not show improvement in measures of oxygenation, the rate of hospitalisation (18% versus 26%, odds ratio 0.70, 95% confidence interval 0.36 to 1.35) or duration of hospitalisation (weighted mean difference 0.12, 95% confidence interval -0.3 to 0.5). REVIEWER'S CONCLUSIONS: Bronchodilators produce modest short-term improvement in clinical scores. This small benefit must be weighed against the costs of these agents.

Glucocorticoids for croup.

BACKGROUND: Since the last meta-analysis in 1989, a number of randomised trials on the benefit of glucocorticoids have been published, resulting in an increasing interest in the use of glucocorticoids to treat outpatients with croup. The objective of this review was to provide evidence to guide clinicians in their treatment of patients with croup, to examine the effectiveness of glucocorticoids in these patients, and to identify areas of uncertainty for future research. OBJECTIVES: To determine the effect of glucocorticoids for children with croup. SEARCH STRATEGY: We searched The Cochrane Controlled Trials Register, MEDLINE (January 1966 to August 1997) and Excerpta Medica/EMBASE (January 1974 to August 1997). We also contacted (by mail) authors of identified croup trials published in the last five years to inquire about other trials, published or unpublished. SELECTION CRITERIA: Meta-analysis of randomised controlled trials that examine the effectiveness of glucocorticoid treatment in children with croup. DATA COLLECTION AND ANALYSIS: Data were extracted using a structured form, which captured patient status (inpatient or outpatient), intervention and control, with the name of the drug, route of administration and dose. Data were also collected on the primary outcome measures comprised of a clinical croup score at baseline (as well as any other subsequent assessment times), length of stay (hours), patients status improved (yes/no), and use of co-interventions. The quality of the trials was assessed using empirically derived items that involved scales and components. Two researchers (TPK, MA) then selected studies as being potentially relevant based on a review of the titles and abstracts, if available. The complete text of these studies was then retrieved. All studies that had been retrieved were reviewed independently by two reviewers (AS, TPK). Data were extracted by one reviewer (MA) and checked for accuracy by a second reviewer (TPK). Two observers independently assessed quality (MA, JK), and inter rater agreement was measured by the intra class correlation. Differences were resolved by consensus. MAIN RESULTS: Twenty-four studies were deemed relevant for inclusion (N=2221). Glucocorticoid treatment was associated with an improvement in the croup severity score at 6 hours with an effect size of -1.0 (95% confidence interval -1.5 to -0.6) and at 12 hours -1.0 (-1.6 to -0. 4); at 24 hours this improvement was no longer significant (-1.0, -2. 0 to 0.1). There was a decrease in the number of adrenaline treatments needed in children treated with glucocorticoids: a decrease of 9% (95% confidence interval 2 to 16%) among those treated with budesonide and of 12% (4 to 20%) among those treated with dexamethasone. There was also a decrease in the length of time spent in accident and emergency (-11 hours, 95% confidence interval -18 to 4 hours), and for inpatients hospital stay was reduced by 16 hours (-31 to 1 hour). Publication bias seems to play a part in these results. REVIEWER'S CONCLUSIONS: Dexamethasone and budesonide are effective in relieving the symptoms of croup as early as 6 hours after treatment. Fewer co-interventions are used and the length of time spent in hospital is decreased in patients treated with glucocorticoids.

A novel multiresistant Streptococcus pneumoniae serogroup 19 clone from Washington State identified by pulsed-field gel electrophoresis and restriction fragment length patterns.

In 1997, a cluster of multiresistant invasive serogroup 19 pneumococcus infections, including two fatalities, was reported in Washington State. Further investigation identified other cases. Fourteen Washington Streptococcus pneumoniae isolates, four from Alaska, and eight isolates from eastern Canada with reduced penicillin susceptibility (MIC of > or =1 microg/ml) were included in the study. Pulsed-field gel electrophoresis (PFGE) with ApaI, SacII, and SmaI restriction enzymes and IS1167 and mef restriction fragment length polymorphism (RFLP) pattern analysis were performed. Twenty of the 26 isolates had identical or related PFGE patterns, with two or all three enzymes, and identical or related IS1167 RFLP patterns, indicating that they were genetically related. These 20 isolates contained the mef gene conferring erythromycin resistance and had identical mef RFLP patterns. The PFGE and RFLP patterns were distinct from those of six multiresistant clones previously described and suggest that a new multiresistant clone has appeared in Washington, Alaska, and eastern Canada. This newly characterized clone should be included in the Pneumococcal Molecular Epidemiology Network.

The effectiveness of glucocorticoids in treating croup: meta-analysis.

OBJECTIVE: To determine the effectiveness of glucocorticoid treatment in children with croup. DESIGN: Meta-analysis of randomised controlled trials that examine the effectiveness of glucocorticoid treatment in children with croup. MAIN OUTCOME MEASURES: Score on scale measuring severity of croup, use of cointerventions (adrenaline (epinephrine), antibiotics, or supplemental glucocorticoids), length of stay in accident and emergency or in hospital, and rate of hospitalisation. RESULTS: Twenty four studies met the inclusion criteria. Glucocorticoid treatment was associated with an improvement in the croup severity score at 6 hours with an effect size of -1.0 (95% confidence interval -1.5 to -0.6) and at 12 hours -1.0 (-1.6 to -0.4); at 24 hours this improvement was no longer significant (-1.0, -2.0 to 0.1). There was a decrease in the number of adrenaline treatments needed in children treated with glucocorticoids: a decrease of 9% (95% confidence interval 2% to 16%) among those treated with budesonide and of 12% (4% to 20%) among those treated with dexamethasone. There was also a decrease in the length of time spent in accident and emergency (-11 hours, 95% confidence interval -18 to 4 hours), and for inpatients hospital stay was reduced by 16 hours (-31 to 1 hour). Publication bias seems to play a part in these results. CONCLUSIONS: Dexamethasone and budesonide are effective in relieving the symptoms of croup as early as 6 hours after treatment. Fewer cointerventions are used and the length of time spent in hospital is decreased in patients treated with glucocorticoids.

Antibiotic prescribing for Canadian preschool children: evidence of overprescribing for viral respiratory infections.

Antibiotic resistance is associated with prior receipt of antibiotics. An analysis of linked computerized databases for physician visits and antibiotic prescriptions was used to examine antibiotic prescribing for different respiratory infections in preschool children in Canada. In 1995, 64% of 61,165 children aged <5 years made 140,892 visits (mean, 3.6 visits per child) for respiratory infections; 74% of children who made visits received antibiotic prescriptions. Antibiotics were prescribed to 49% of children with upper respiratory tract infection, 18% with nasopharyngitis, 78% with pharyngitis or tonsillitis, 32% with serous otitis media, 80% with acute otitis media, 61% with sinusitis, 44% with acute laryngitis or tracheitis, and 24% with influenza. Acute otitis media accounted for 33% of all visits and 39% of all antibiotic prescriptions. The estimated Canadian-dollar cost of overprescribing was $423,693, or 49% of the total cost of antibiotics ($859,893) used in this group. This population-based study confirms antibiotic overprescribing in Canada.

Streptococcus pneumoniae carriage in children attending 59 Canadian child care centers. Toronto Child Care Centre Study Group.

OBJECTIVES: To determine the prevalence of Streptococcus pneumoniae nasopharyngeal carriage, antibiotic resistance patterns, and serotypes; to examine the variability of microbiological findings between child care centers; and to determine risk factors for antibiotic resistance. DESIGN: Point prevalence survey. SETTING: Licensed child care centers in Toronto, Ontario. PARTICIPANTS: Healthy children attending the centers. MAIN OUTCOME MEASURES: Prevalence (simple and adjusted for clustering) of carriage, antibiotic resistance, and serotypes; multivariate analysis of risk factors for resistance. RESULTS: Of 1322 children from 59 centers, 586 (44.3%) carried 599 S. pneumoniae isolates. On the day of study, 129 (10.7%) of 1203 children for whom a questionnaire was completed were taking antibiotics and 336 (227.9%) had taken them in the previous month. Decreased susceptibility to penicillin was found in 102 isolates (17.0%) and 82 (13.7%) were resistant to multiple antibiotics. The most common serotypes, in order, were 6B, 23F, 6A, 19F, 14, 11A, and 19A, composing 78% of all isolates. Microbiological results from individual centers were variable, but the overall prevalence of carriage, antibiotic resistance, and serotypes was not significantly different when adjusted for effects of clustering within centers. Multiple logistic regression determined that age younger than 24 months and antibiotic use within the previous month were significant risk factors for carriage of S. pneumoniae resistant to penicillin, sulfamethoxazole-trimethoprim, and erythromycin. CONCLUSIONS: Efforts to reduce antibiotic use in children should be particularly directed toward young children attending child care centers. Studies of infectious diseases in child care centers should consider clustering of pathogens or factors promoting transmission within centers that may result in variability between centers.

The effectiveness of glucocorticoids in treating croup: meta-analysis.

OBJECTIVE: To determine the effectiveness of glucocorticoid treatment in children with croup. DESIGN: Meta-analysis of randomized controlled trials that examine the effectiveness of glucocorticoid treatment in children with croup. MAIN OUTCOME MEASURES: Score on scale measuring severity of croup,use of co-interventions (epinephrine, antibiotics, or supplemental glucocorticoids), length of stay in the emergency department or the hospital, and rate of hospitalization. RESULTS: Twenty-four studies met the inclusion criteria. Glucocorticoid treatment was associated with an improvement in the croup severity score at 6 hours with an effect size of -1.0 (95% confidence interval [CI] -1.5 to -0.6) and at 12 hours -1.0 (-1.6 to -0.4); at 24 hours, this improvement was no longer significant (-1.0, -2.0 to -0.1). There was a decrease in the number of epinephrine treatments needed in children treated with glucocorticoids: a decrease of 9% (95% CI 2% to 16%) among those treated with budesonide and of 12% (4% to 20%) among those treated with dexamethasone. There was also a decrease in the length of time spent in the emergency department (-11 hours, 95% CI -18 to 4 hours) and, for inpatients, hospital stay was reduced by 16 hours (-31 to 1 hour). Publication bias seems to play a part in these results. CONCLUSIONS: Dexamethasone and budesonide are effective in relieving the symptoms of croup as early as 6 hours after treatment. Fewer co-interventions are used, and the length of time spent in the hospital is decreased in patients treated withglucocorticoids.

Antibiotic-resistant Streptococcus pneumoniae. Implications for medical practice.

OBJECTIVE: To review the definition and prevalence of antibiotic-resistant Streptococcus pneumoniae, its links with antibiotic prescribing, data on antibiotic prescribing and prescribing appropriateness, and evidence-based treatment guidelines for common respiratory tract syndromes. QUALITY OF EVIDENCE: Primary studies consist of cross-sectional surveys and case-control studies. Treatment guidelines are based on clinical trials, meta-analyses, and cohort studies. Study designs were appropriate for the specific study questions. MAIN FINDINGS: The increasing prevalence of penicillin-resistant S pneumoniae is concurrent with increasing antibiotic prescribing. Individual patients show a twofold to ninefold increase in nasopharyngeal carriage of resistant bacteria or invasion with resistant bacteria (among those who have received antibiotics in the preceding 3 months). Cross-sectional data as well as data from medicaid and drug databases attest to overprescribing of antibiotics for respiratory tract infections. Physician surveys and focus groups blame this on parental pressure for antibiotic prescriptions. However, parents in focus groups and surveys deny they pressure their physicians and indicate their main purpose for office visits is to obtain a diagnosis and to seek reassurance that their children are not seriously ill. Evidence-based guidelines suggest treatment strategies that would reduce antibiotic prescribing. CONCLUSIONS: The few antibiotics that can be used with resistant organisms are expensive and are increasingly being needed. To control the rise of antibiotic resistance, it is important to limit antibiotic overprescribing.

Predictors and outcome of admission for invasive Streptococcus pneumoniae infections at a Canadian children's hospital.

Rates of admission for invasive Streptococcus pneumoniae infection in children vary considerably between institutions. We performed a retrospective study to investigate factors used in the decision to admit patients with invasive S. pneumoniae infection to Alberta Children's Hospital. Of 254 patients who were initially assessed in the emergency department, 38.2% were admitted to the hospital. Significant risk factors for admission as determined by a logistic regression model included murmur (odds ratio [OR], 18.98; 95% confidence interval [CI], 4.08-88.23), focal infection (OR, 11.41; 95% CI, 5.07-25.67), and older age (OR, 2.72; 95% CI, 1.03-7.17). Higher hemoglobin level (OR, 0.96; 95% CI, 0.93-0.99) and temperature of > 38.5 degrees C (OR, 0.39; 95% CI, 0.18-0.85) were associated with a lower risk of admission. Two patients died (case-fatality rate, 0.7%). Despite the low rate of admission for invasive S. pneumoniae infections at our hospital, the mortality rate was comparable with those at institutions with higher rates of admission, thus suggesting that the factors we identified may be useful in deciding whether to admit patients with (or who are at high risk for) invasive S. pneumoniae infections.

Prevalence and characterization of the mechanisms of macrolide, lincosamide, and streptogramin resistance in isolates of Streptococcus pneumoniae.

Of a total of 147 erythromycin-resistant Streptococcus pneumoniae isolates, 64 (43.5%) were resistant to erythromycin, clindamycin, and streptogramin B (MLSB phenotype), 57 of which possessed the ermB gene. Eighty-two (55.8%) were resistant to erythromycin alone (M phenotype), 81 of which possessed the mefE gene. One was erythromycin and streptogramin B resistant but susceptible to clindamycin (MS phenotype) and possessed neither the erm gene nor the mefE gene.

The use of Streptococcus pneumoniae nasopharyngeal isolates from healthy children to predict features of invasive disease.

BACKGROUND: The role of sampling nasopharyngeal carriage isolates of Streptococcus pneumoniae to determine characteristics of isolates causing invasive disease has not been established. METHODS: Data were compared from two 1995 studies of S. pneumoniae in Metropolitan Toronto and Peel Region (population, 3.1 million). The first was a prospective survey of nasopharyngeal (NP) carriage in child care centers. The second was a prospective surveillance for all cases of invasive disease. RESULTS: There were 545 NP S. pneumoniae isolates obtained from 532 children and 96 cases of invasive S. pneumoniae disease in children. The prevalences of reduced antibiotic susceptibility in the NP carriage and invasive studies, respectively, were: penicillin (16% vs. 11%, P=0.29); erythromycin (12% vs. 7%, P=0.25); and multiresistant (16% vs. 12%, P=0.34). The power to rule out a difference between the groups was <30% for each comparison. Trimethoprim/sulfamethoxazole resistance was more common in NP carriage isolates than invasive isolates (38% vs. 23%, P=0.02). Serotype 14 was more common in invasive isolates, whereas serogroup 6 was more common in NP carriage isolates. Antibiotic-resistant isolates were predominantly serogroups 6, 19 and 23 in both studies. CONCLUSIONS: Nasopharyngeal carriage isolates of S. pneumoniae reflect the antibiotic susceptibility rates of invasive isolates found in the same period for most antibiotics. However, even a large study like this may have limited power to detect a difference. The most common NP carriage serotypes are the same as the invasive isolates, although the rank order of specific serotypes is different. Routine surveys of S. pneumoniae NP carriage are not feasible because of the cost of serotyping and limited power of the observations, unless sample sizes are extremely large.

The superbugs: evolution, dissemination and fitness.

Since the introduction of antibiotics, bacteria have not only evolved elegant resistance mechanisms to thwart their effect, but have also evolved ways in which to disseminate themselves or their resistance genes to other susceptible bacteria. During the past few years, research has revealed not only how such resistance mechanisms have been able to evolve and to rapidly disseminate, but also how bacteria have, in some cases, been able to adapt to this new burden of resistance with little or no cost to their fitness. Such adaptations make the control of these superbugs all the more difficult.