Derek R. MacFadden

Assessment of the potential for international dissemination of Ebola virus via commercial air travel during the 2014 west African outbreak

Summary Background The WHO declared the 2014 west African Ebola epidemic a public health emergency of international concern in view of its potential for further international spread. Decision makers worldwide are in need of empirical data to inform and implement emergency response measures. Our aim was to assess the potential for Ebola virus to spread across international borders via commercial air travel and assess the relative efficiency of exit versus entry screening of travellers at commercial airports. Methods We analysed International Air Transport Association data for worldwide flight schedules between Sept 1, 2014, and Dec 31, 2014, and historic traveller flight itinerary data from 2013 to describe expected global population movements via commercial air travel out of Guinea, Liberia, and Sierra Leone. Coupled with Ebola virus surveillance data, we modelled the expected number of internationally exported Ebola virus infections, the potential effect of air travel restrictions, and the efficiency of airport-based traveller screening at international ports of entry and exit. We deemed individuals initiating travel from any domestic or international airport within these three countries to have possible exposure to Ebola virus. We deemed all other travellers to have no significant risk of exposure to Ebola virus. Findings Based on epidemic conditions and international flight restrictions to and from Guinea, Liberia, and Sierra Leone as of Sept 1, 2014 (reductions in passenger seats by 51% for Liberia, 66% for Guinea, and 85% for Sierra Leone), our model projects 2·8 travellers infected with Ebola virus departing the above three countries via commercial flights, on average, every month. 91 547 (64%) of all air travellers departing Guinea, Liberia, and Sierra Leone had expected destinations in low-income and lower-middle-income countries. Screening international travellers departing three airports would enable health assessments of all travellers at highest risk of exposure to Ebola virus infection. Interpretation Decision makers must carefully balance the potential harms from travel restrictions imposed on countries that have Ebola virus activity against any potential reductions in risk from Ebola virus importations. Exit screening of travellers at airports in Guinea, Liberia, and Sierra Leone would be the most efficient frontier at which to assess the health status of travellers at risk of Ebola virus exposure, however, this intervention might require international support to implement effectively. Funding Canadian Institutes of Health Research.

Sex differences in implantable cardioverter-defibrillator outcomes: findings from a prospective defibrillator database.

BACKGROUND Sex differences in the use and outcomes of implantable cardioverter-defibrillators (ICDs) have not been fully studied. OBJECTIVE To examine potential sex differences in ICD implantation and device outcomes. DESIGN Health payer-mandated, prospective study of patients referred for ICD implantation, with comprehensive, longitudinal follow-up for complications, deaths, and device outcomes. SETTING 18 ICD implantation and follow-up centers in Ontario, Canada. PATIENTS 6021 patients (4733 men) referred for ICD implantation from February 2007 to July 2010. MEASUREMENTS Multivariate-adjusted ICD implantation rate, complications up to day 45, multivariate-adjusted complications, device outcomes (including appropriate shocks and therapies), and deaths occurring during 1-year follow-up. RESULTS Rates of ICD implantation were similar in men and women (relative risk, 0.99 [95% CI, 0.97 to 1.02]; P = 0.60). However, women were significantly more likely to experience major complications by 45 days (odds ratio, 1.78 [CI, 1.24 to 2.58]; P = 0.002) and 1 year (hazard ratio [HR], 1.91 [CI, 1.48 to 2.47]; P < 0.001) after implantation. Occurrence of any major or minor complication was also increased in women at both 45-day follow-up (odds ratio, 1.50 [CI, 1.12 to 2.00]; P = 0.006) and 1-year follow-up (HR, 1.55 [CI, 1.25 to 1.93]; P < 0.001). After implantation, women were less likely than men to receive appropriate ICD shock (HR, 0.69 [CI, 0.51 to 0.93]; P = 0.015) or appropriate therapy via shock or antitachycardia pacing (HR, 0.73 [CI, 0.59 to 0.90]; P = 0.003). Total mortality among defibrillator recipients did not differ between men and women (HR, 1.00 [CI, 0.64 to 1.55]; P = 0.99). LIMITATION The differential effects of sex on prereferral events were not examined. CONCLUSION Although ICD implantation rates were similar after referral to an electrophysiologist, women who underwent ICD implantation had greater risks for complications and were less likely to experience appropriate ICD-delivered therapies than men. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research and Ontario Ministry of Health and Long-Term Care.

Impact of Reported Beta-Lactam Allergy on Inpatient Outcomes: A Multicenter Prospective Cohort Study

BACKGROUND Reported allergy to beta-lactam antibiotics is common and often leads to unnecessary avoidance in patients who could tolerate these antibiotics. We prospectively evaluated the impact of these reported allergies on clinical outcomes. METHODS We conducted a trainee-led prospective cohort study to determine the burden and clinical impact of reported beta-lactam allergy on patients seen by infectious diseases consultation services at 3 academic hospitals. The primary outcome was a composite measure of readmission for the same infection, acute kidney injury, Clostridium difficile infection, or drug-related adverse reactions requiring discontinuation. Predictors of interest were history of beta-lactam allergy and receipt of preferred beta-lactam therapy. RESULTS Among 507 patients, 95 (19%) reported beta-lactam allergy; preferred therapy was a beta-lactam in 72 (76%). When beta-lactam therapy was preferred, 25 (35%) did not receive preferred therapy due to their report of allergy even though 13 (52%) reported non-severe prior reactions. After adjustment for confounders, patients who did not receive preferred beta-lactam therapy were at greater risk of adverse events (adjusted odds ratio [aOR], 3.1; 95% confidence interval [CI], 1.28-7.89) compared with those without reported allergy. In contrast, patients who received preferred beta-lactam therapy had a similar risk of adverse events compared with patients not reporting allergy (aOR, 1.33; 95% CI, .62-2.87). CONCLUSIONS Avoidance of preferred beta-lactam therapy in patients who report allergy is associated with an increased risk of adverse events. Development of inpatient programs aimed at accurately identifying beta-lactam allergies to safely promote beta-lactam administration among these patients is warranted.

Development of a geometrically accurate imaging protocol at 3 Tesla MRI for stereotactic radiosurgery treatment planning.

The purpose of this study is to develop a geometrically accurate imaging protocol at 3 T magnetic resonance imaging (MRI) for stereotactic radiosurgery (SRS) treatment planning. In order to achieve this purpose, a methodology is developed to investigate the geometric accuracy and stability of 3 T MRI for SRS in phantom and patient evaluations. Forty patients were enrolled on a prospective clinical trial. After frame placement prior to SRS, each patient underwent 3 T MRI after 1.5 T MRI and CT. MR imaging protocols included a T1-weighted gradient echo sequence and a T2-weighted spin echo sequence. Phantom imaging was performed on 3 T prior to patient imaging using the same set-up and imaging protocols. Geometric accuracy in patients and phantoms yielded comparable results for external fiducial reference deviations and internal landmarks between 3 T and 1.5 T MRI (mean ≤ 0.6 mm; standard deviation ≤ 0.3 mm). Mean stereotactic reference deviations between phantoms and patients correlated well (T1: R = 0.79; T2: R = 0.84). Statistical process control analysis on phantom QA data demonstrated the stability of our SRS imaging protocols, where the geometric accuracy of the 3 T SRS imaging protocol is operating within the appropriate tolerance. Our data provide evidence supporting the spatial validity of 3 T MRI for targeting SRS under imaging conditions investigated. We have developed a systematic approach to achieve confidence on the geometric integrity of a given imaging system/technique for clinical integration in SRS application.

Evaluating sex differences in population-based utilization of implantable cardioverter-defibrillators: Role of cardiac conditions and noncardiac comorbidities

BACKGROUND The influence of age and comorbidities on sex-specific implantable cardioverter-defibrillator (ICD) use for primary or secondary prevention is undefined. OBJECTIVE The purpose of this study was to investigate the influence of age and comorbidities on sex-specific ICD use. METHODS Sex disparities and sex-specific trends in ICD implantation according to indication in patients with cardiac arrest (1998-2007) in Ontario, Canada, were examined. Use of ICDs for primary prevention in patients with myocardial infarction (2002-2007) or heart failure (2005-2007) also was examined. RESULTS Among 9,246 eligible secondary prevention patients (age 66.3 +/- 14.3 years; 3,577 women [39%]) with cardiac arrest, men were more likely to undergo ICD implantation, with an age-, comorbidity-, and arrhythmia-adjusted hazard ratio (HR) of 1.92 (95% confidence interval [CI]: 1.66-2.23). Among 105,516 patients with myocardial infarction (age 68.3 +/- 12.7 years; 42,987 women [41%]), men were threefold more likely to undergo ICD implantation, with an adjusted HR of 3.00 (95% CI: 2.53-3.55). Among 61,160 patients with heart failure (age 76.2 +/- 12.0 years; 31,575 women [52%]), ICD implantation was more likely in men, with an adjusted HR of 3.01 (95% CI: 2.59-3.50). The odds of ICD implant for secondary prevention increased over time by 21% (95% CI: 13%-30%) in women and by 6% (95% CI: 2%-11%) in men, but rates of ICD use in men for primary prevention indications were persistently higher. CONCLUSION Men were more likely to undergo defibrillator implant than were women for primary and secondary prevention. Age and comorbidities did not account for the observed sex differences. Although sex differences in secondary prevention are declining over time, disparities in primary prevention persist.

CLINICAL EVALUATION OF STEREOTACTIC TARGET LOCALIZATION USING 3-TESLA MRI FOR RADIOSURGERY PLANNING

PURPOSE Increasing the magnetic resonance imaging (MRI) field strength can improve image resolution and quality, but concerns remain regarding the influence on geometric fidelity. The objectives of the present study were to spatially investigate the effect of 3-Tesla (3T) MRI on clinical target localization for stereotactic radiosurgery. METHODS AND MATERIALS A total of 39 patients were enrolled in a research ethics board-approved prospective clinical trial. Imaging (1.5T and 3T MRI and computed tomography) was performed after stereotactic frame placement. Stereotactic target localization at 1.5T vs. 3T was retrospectively analyzed in a representative cohort of patients with tumor (n = 4) and functional (n = 5) radiosurgical targets. The spatial congruency of the tumor gross target volumes was determined by the mean discrepancy between the average gross target volume surfaces at 1.5T and 3T. Reproducibility was assessed by the displacement from an averaged surface and volume congruency. Spatial congruency and the reproducibility of functional radiosurgical targets was determined by comparing the mean and standard deviation of the isocenter coordinates. RESULTS Overall, the mean absolute discrepancy across all patients was 0.67 mm (95% confidence interval, 0.51-0.83), significantly <1 mm (p < .010). No differences were found in the overall interuser target volume congruence (mean, 84% for 1.5T vs. 84% for 3T, p > .4), and the gross target volume surface mean displacements were similar within and between users. The overall average isocenter coordinate discrepancy for the functional targets at 1.5T and 3T was 0.33 mm (95% confidence interval, 0.20-0.48), with no patient-specific differences between the mean values (p >.2) or standard deviations (p >.1). CONCLUSION Our results have provided clinically relevant evidence supporting the spatial validity of 3T MRI for use in stereotactic radiosurgery under the imaging conditions used.

Predictive Utility of Prior Positive Urine Cultures

BACKGROUND A patients prior urine cultures are often considered when choosing empiric antibiotic therapy for a suspected urinary tract infection. We sought to evaluate how well previous urine cultures predict the identity and susceptibility of organisms in a patients subsequent urine cultures. METHODS We conducted a multinational, multicenter, retrospective cohort study, including 22 019 pairs of positive urine cultures from 4351 patients across 2 healthcare systems in Toronto, Ontario, and Chicago, Illinois. We examined the probability of the same organism being identified from the same patients positive urine culture as a function of time elapsed from the previous positive urine specimen; in cases where the same organism was identified we also examined the likelihood of the organism exhibiting the same or better antimicrobial susceptibility profile. RESULTS At 4-8 weeks between cultures, the correspondence in isolate identity was 57% (95% confidence interval [CI], 55%-59%), and at >32 weeks it was 49% (95% CI, 48%-50%), still greater than expected by chance (P < .001). The susceptibility profile was the same or better in 83% (95% CI, 81%-85%) of isolate pairs at 4-8 weeks, and 75% (95% CI, 73%-77%) at >32 weeks, still greater than expected by chance (P < .001). Despite high local rates of ciprofloxacin resistance in urine isolates across all patients (40%; 95% CI, 39.5%-40.5%), ciprofloxacin resistance was <20% among patients with a prior ciprofloxacin sensitive organism and no subsequent fluoroquinolone exposure. CONCLUSIONS A patients prior urine culture results are useful in predicting the identity and susceptibility of a current positive urine culture. In areas of high fluoroquinolone resistance, ciprofloxacin can be used empirically when prior urine culture results indicate a ciprofloxacin-susceptible organism and there has been no history of intervening fluoroquinolone use.

The Opening and Closing of Empiric Windows: The Impact of Rapid Microbiologic Diagnostics

TO THE EDITOR—With the advent of rapid diagnostic techniques for pathogen identification, clinicians are encountering increasing windows of time when they are aware of an infecting organism’s species without yet knowing its susceptibilities [1, 2]. We believe that it is worthwhile to formally recognize these empiric windows in the management of infectious diseases (Figure 1). These windows include infectious syndrome–guided therapy (empiric window 1), Gram stain morphology–guided therapy (empiric window 2), and pathogen-guided therapy (empiric window 3), before, finally, susceptibility-guided therapy. Rapid speciation methods including matrix-assisted laser desorption/ionization–time of flight, and, potentially, polymerase chain reaction–based methods, could close the empiric window 2 by half (from 54 to 24 hours), while opening empiric window 3 much more widely (from 3 hours up to 21 hours) [1, 2, 4]. The alteration of these empiric windows can have significant impact on patient outcomes and may pose new challenges for treating physicians. Empiric window 2 has historically been a critical time period where clinicians may adapt their treatment approach based on Gram staining. Having less time between the Gram stain and pathogen identification may lead clinicians to wait for speciation results rather than having to make more frequent antimicrobial changes. Empiric window 3, traditionally a small window between speciation and susceptibility results, will be increased with rapid speciation techniques, and this means that clinicians have time to adapt their empiric therapy accordingly. This will suddenly make institutional species-specific antibiograms much more clinically useful. Moreover, clinicians may be able to more quickly discontinue therapy following identification of obvious culture contaminants (eg, Corynebacterium species), or more rapidly de-escalate therapy after identification of organisms with predictable susceptibilities (eg, Listeria monocytogenes). In some instances, empiric window 3 will cause pathogen-guided escalation prior to susceptibility-guided de-escalation of empiric therapy (eg, Enterococcus species or Pseudomonas species) [1].

Utility of prior screening for methicillin-resistant Staphylococcus aureus in predicting resistance of S. aureus infections

Background: Screening for methicillin-resistant Staphylococcus aureus (MRSA) is intended to reduce nosocomial spread by identifying patients colonized by MRSA. Given the widespread use of this screening, we evaluated its potential clinical utility in predicting the resistance of clinical isolates of S. aureus. Methods: We conducted a 2-year retrospective cohort study that included patients with documented clinical infection with S. aureus and prior screening for MRSA. We determined test characteristics, including sensitivity and specificity, of screening for predicting the resistance of subsequent S. aureus isolates. Results: Of 510 patients included in the study, 53 (10%) had positive results from MRSA screening, and 79 (15%) of infecting isolates were resistant to methicillin. Screening for MRSA predicted methicillin resistance of the infecting isolate with 99% (95% confidence interval [CI] 98%–100%) specificity and 63% (95% CI 52%–74%) sensitivity. When screening swabs were obtained within 48 hours before isolate collection, sensitivity increased to 91% (95% CI 71%–99%) and specificity was 100% (95% CI 97%–100%), yielding a negative likelihood ratio of 0.09 (95% CI 0.01–0.3) and a negative predictive value of 98% (95% CI 95%–100%). The time between swab and isolate collection was a significant predictor of concordance of methicillin resistance in swabs and isolates (odds ratio 6.6, 95% CI 1.6–28.2). Interpretation: A positive result from MRSA screening predicted methicillin resistance in a culture-positive clinical infection with S. aureus. Negative results on MRSA screening were most useful for excluding methicillin resistance of a subsequent infection with S. aureus when the screening swab was obtained within 48 hours before collection of the clinical isolate.

A passage from India: Association between air traffic and reported cases of New Delhi Metallo-beta-lactamase 1 from 2007 to 2012.

BACKGROUND Highly transmissible genes encoding resistance to carbapenems have demonstrated global spread. The New Delhi Metallo-beta-lactamase 1 gene is hypothesized to have originated in India, with subsequent dissemination by colonized or infected travelers. METHOD We conducted an ecological study evaluating the association between the cumulative air traffic departing India between 2007 and 2012 and published cases of NDM-1. Receiver operator characteristic curves were generated as well as multivariate logistic regression models. 193 countries with complete flight and World Bank data were included in the analysis. RESULTS Receiver operator characteristic curves (ROC) of the dichotomous outcome of a published case of NDM-1 were generated, yielding an unadjusted area under the curve (AUC) of 0.88 and adjusted AUC of 0.85. The unadjusted odds ratio of having a reported case of NDM-1, for every percentage increase in cumulative air traffic departing India, was 2.3 (95% CI 1.4 to 3.7) and adjusted was 2.0 (95% CI 1.2 to 3.4). CONCLUSIONS We demonstrate that flows of international travelers departing India by air is associated with published NDM-1 cases, globally. Countries with high passenger flight traffic from India with no reported cases of NDM-1 may be at increased risk of having unreported transmission of NDM-1.