Derek R. MacFadden

Predicted probabilities of antibiotic susceptibility to known or suspected pathogens can be used to support antibiotic selection. Patient demographic, clinical, and prior microbiologic history can be used to generate location-specific prediction models. For three Canadian tertiary care institutions we fit and evaluated models for predicting Gram-negative antibiotic susceptibilities to common antimicrobial agents based on previously established model structures. A web-based application was developed to permit visualization of antibiotic susceptibility predictions and support antibiotic decision-making.

Clinical decision support tools can curb unnecessary antibiotic use, but success depends on more than technology. Here, we explore behavioral, equity, and governance challenges in tackling antimicrobial resistance, and why “better, not just fewer” prescriptions are essential.

Introduction: As antibiotic resistant organisms and infections continue to proliferate globally, it becomes increasingly difficult to select empiric antibiotic therapy, particularly in patients who stand to benefit from early adequate treatment. The inappropriate treatment of suspected infection, including sepsis, can be both too narrow and too broad. There is a need to optimize and tailor selection of antibiotic therapy to each patient, such that those at risk for infections due to antibiotic resistant organisms receive broader therapy, and those that are not at risk receive narrower antibiotic therapy. By helping clinicians select the right antibiotic for each individual patient we can potentially reduce unnecessarily broad antibiotic prescribing while preserving (and potentially improving) adequacy of treatment. Individualized clinical prediction models and decision support interventions are promising approaches that can meet these needs by better defining patient risk for antibiotic resistant or susceptible infections, but rigorous prospective evaluations are needed to confirm their utility. Methods: We propose a two-period two-sequence non-blinded cross-sectional cluster randomized cross-over trial of an individualized antibiotic prescribing decision support intervention, administered by antibiotic stewardship pharmacists, for providers treating hospitalized patients with suspected infection including sepsis. The trial is taking place at 3 hospitals in Ontario, Canada, with clusters defined as medical, surgical, and critical care services. Eligible patients are adults with suspected infection characterized by initiation of a broad-spectrum antibiotic and recent collection of blood cultures. This decision support intervention will be based on a combination of proven decision heuristics (for Gram-positive organisms), modelled predicted susceptibilities (for Gram-negative organisms), and well-defined syndromes, that are individualized to the patient. Our primary outcome will be whether or not patients are de-escalated from their initial empiric regimen at 48 hours. The target sample size is 18 clusters with anticipated data from 1,440 patients, designed to achieve 80% power to detect an absolute increase in de-escalation at 48 hours of 7. 5%. Secondary outcomes include adequacy of therapy, process measures, and safety. Analysis: The primary and secondary outcomes will be analyzed at the patient-level using generalized linear mixed effects regression with fixed effects for treatment and period to account for the cross-over design, as well as fixed effects for the stratification factors and a priori patient risk factors to improve power and efficiency. Cluster and cluster-period random effects will be included to account for within-period and between-period intracluster correlation and the Kenward-Roger correction will be applied to minimize small sample bias. The primary effect estimate will be presented as a risk ratio with 95% confidence interval. Ethics and Dissemination: This trial has research ethics board approval at all participating sites and adheres to the Ottawa Statement ethics guidelines. The study is registered with clinicaltrials.gov, and the results will be published open access in a peer-reviewed journal. Registration: Clinicaltrials.gov , NCT06103500 . STRENGTHS AND LIMITATIONS: IDEAS-CRXO is a cluster randomized cross-over trial of a pharmacist administered decision support intervention for antibiotic prescribing in patients with suspected infection. The intervention is based upon a generalizable algorithm incorporating Gram-positive heuristics, Gram-negative modelled susceptibility, and local well-defined syndrome treatment guidelines. The primary outcome is a relevant measure for antibiotic stewardship - antibiotic de-escalation from the initial empiric index regimen at 48 hours from receipt of antibiotics. Secondary outcomes are focused on other clinical, process, and safety measures. This rigorous cluster randomized cross-over trial will be conducted with 18 clusters (across three institutions) which will achieve 80% power in a two-period two-sequence design to detect a clinically important absolute difference of 7.5% in the primary outcome at a 5% two-sided significance level. This study could be impacted by treatment contamination, however the cluster design will limit this potential source of bias.

Introduction: The health care burden of chronic hepatitis B virus (CHB) infection can be reduced by appropriate workup, treatment, and monitoring. Methods: As a primary objective, we determined whether adequate initial hepatitis B virus (HBV) laboratory workup in CHB patients is associated with improved CHB complications risk. Secondary outcomes assessed included: mortality, hospitalization, emergency department, and liver specialist visits. We conducted a retrospective cohort study from 1 January 2012 to 31 December 2018. Participants were followed from 12 months post index event until outcome occurrence, death, loss of eligibility, or 31 March 2023. Health administrative data from Ontario, Canada was utilized. The study cohort included individuals with at least one positive result of either hepatitis B surface antigen, hepatitis B e antigen, or HBV DNA viral load documented during the study window. The exposure of interest was defined as adequate laboratory workup, defined as having subsequent quantitative HBV DNA, and alanine aminotransferase testing completed within 12 months of the index event. CHB-related complications were assessed using previously validated diagnostic codes. Modified Poisson regression modelling was used to estimate relative risks. Results: The study cohort consisted of 30,794 CHB patients, with a mean age 45.7 years. The majority were male (53.5%) and within the lowest two income quintiles (50.2%). In total, 68.0% underwent adequate workup. Individuals with adequate workup were more likely to be older, male, urban based, and of the highest racialized and newcomer populations quintile. The risk for CHB complications was 1.50 (95% CI 1.36–1.65) times greater among those with adequate workup. By multivariable analysis, adequate workup was associated with a lower risk of mortality (RR 0.78; 95% CI 0.69–0.87), all-cause hospitalizations (RR 0.77; 95% CI 0.74–0.80), all-cause (RR 0.77; 95% CI 0.75–0.78), and liver-related (RR 0.67; 95% CI 0.60–0.75) ED visits. Conclusions: Adequate CHB clinical workup is associated with improved patient outcomes. Our findings advocate for the comprehensive evaluation of CHB patients using key laboratory tests to optimize clinical management and improve long-term health outcomes. We identified gaps in the workup of young adults, females, and those residing in rural settings, which should be addressed to ensure equity of HBV care.

Ongoing viral evolution is a key driver of global pandemics, such as COVID-19, contributing to the repeated emergence and spread of new variants of concern. Identifying emerging viral variants is crucial for controlling the spread of infection; however, patient testing is not always feasible, and clinical samples are not routinely sequenced. As a result, new approaches, such as environmental-based surveillance, are needed for monitoring genetic diversity. Floor swabs provide greater spatial resolution than other environmental sampling approaches, but pose challenges for genomic analyses due to microbial RNA/DNA yields. We investigate the potential of obtaining whole-genome diversity data from floor swab samples to detect circulating lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Floor swabs (n=23) were collected and sequenced from public locations in Ottawa, Canada, during December 2022, and were compared with contemporaneous human samples. Low biomass recovery remained a challenge, as approximately half of the swabs did not yield sufficient genetic material for analysis. The most commonly identified lineages from the floor swabs were XBB, while B (12.5%) and BA (12.5%) lineages appeared less frequently. In contrast, swab results from humans most often identified BQ (49.3%), BA (23.8%) and BF (17.8%), with XBB detected at a lower prevalence (2.7%). XBB became the dominant lineage in the region in the month following floor swab collection, suggesting that floor swabs may offer early signals of emerging outbreaks in comparison with hospital-based clinical sampling. This may suggest a role for floor swabs in outbreak prediction; however, larger studies are needed to validate this approach.

Objectives: Gram negative bloodstream infections (GN BSI) are a leading cause of mortality worldwide, and antibiotic treatment approaches remain understudied. BALANCE+ is a perpetual Bayesian adaptive platform trial to test multiple treatment questions for hospitalised patients with GN BSI. The vanguard phase objective was to test the feasibility of the main trial. Design: Adaptive platform trial with five initial domains of investigation, each with open label 1:1 randomisation. Setting: Ten hospitals across four Canadian provinces. Participants: Individuals admitted to hospital with blood cultures yielding Gram negative bacteria. Interventions: The five initial domains of investigation included: antibiotic de-escalation versus no de-escalation; oral transition to beta-lactam versus non-beta-lactam treatment; routine versus no routine follow-up blood cultures (FUBCs); central vascular catheter replacement versus retention; and, ceftriaxone versus carbapenem treatment for low risk AmpC organisms. Primary outcome measures: Domain-specific recruitment rates and protocol adherence. Results: During the vanguard phase, 719 patients were screened, of whom 563 (78.3%) were eligible, with 179 (31.8%) enrolled into the platform. The platform recruitment rate was 1.37 patients/site-week. Recruitment varied by domain: routine versus no FUBC domain 1.23 patients/site-week; oral beta-lactam versus non-beta-lactam domain 0.48; de-escalation versus no de-escalation domain 0.28; low risk AmpC domain 0.02; catheter replacement versus retention domain 0.01. Domain specific protocol adherence rates were 145/158 (91.8%) for routine versus no routine FUBC, 53/60 (88.3%) for oral beta-lactam versus non-beta-lactam, 26/33 (78.8%) for de-escalation versus no de-escalation, 3/3 (100%) for low risk AmpC, and 0/1 (0%) for line replacement versus retention. There was complete ascertainment of all study outcomes in hospital 170/170 (100%) and near complete ascertainment at 90 days 162/170 (95.3%). Conclusions: The vanguard phase demonstrated overall trial feasibility by recruitment rate and protocol adherence, with differences across interventions, leading to a transition to the main BALANCE+ platform trial with minimal protocol modifications. Trial registration number: NCT05893147 .

Background: Colonization with enteropathogens such as Clostridioides difficile ( C. difficile) has been linked to clinical infection with these same organisms. C. difficile infection (CDI) is associated with increased morbidity and mortality in patients undergoing hematopoietic cell transplantation (HCT). The study aims to evaluate the utility of existing C. difficile stool detection methods used during pre-transplant planning to identify individuals at high risk of developing CDI within 3 months post-transplant. Methods: A prospective cohort study of patients undergoing HCT at a large quaternary care centre was conducted to assess the impact of baseline C. difficile colonization on downstream CDI outcomes. Baseline stool samples were collected prior to admission for conditioning chemotherapy, which were evaluated for C. difficile colonization using routine, short–turnaround-time clinical approaches by performing glutamine dehydrogenase (GDH) enzyme immunoassay (EIA) and toxin B gene (tcdB) polymerase chain reaction (PCR). Clinical data and outcomes were reviewed 3 months post-transplant. Test characteristics for using baseline C. difficile colonization as a screening tool for predicting subsequent CDI were calculated. Results: Sixty patients were enrolled. The prevalence of C. difficile colonization (GDH positive) among patients undergoing HCT was 10% (6/60). Ten patients developed CDI within 3 months post-transplant, 50% of whom were colonized at baseline. Among the colonized patients, 83% (5/6) developed CDI during the follow-up period. Asymptomatic C. difficile colonization pre-admission had a 98% specificity (95% CI, 89% to 100%), 50% sensitivity (95% CI, 19% to 81%), 83% positive predictive value (95% CI, 36%–100%), and 91% negative predictive value (95% CI, 80% to 97%) for developing subsequent CDI. Conclusions: Pre-admission C. difficile screening could support targeted prophylactic strategies for patients at risk of developing CDI, and this approach warrants further evaluation.

Built environment surveillance has shown promise for monitoring COVID-19 burden at granular geographic scales, but its utility for surveillance across larger areas and populations is unknown. Our study aims to evaluate the role of built environment detection of SARS-CoV-2 for the surveillance of COVID-19 across broad geographies and populations. We conducted a prospective city-wide sampling study to examine the relationship between SARS-CoV-2 on floors and COVID-19 burden. We used non-parametric correlation analyses and linear models to evaluate associations between SARS-CoV-2 signals and COVID-19 outcomes, across multiple locations/populations over time. Sampling sites included schools, libraries, and emergency departments in the capital city of Ottawa, Canada, from October 2022 to March 2023. Floor sampling was performed across spaces, and outcomes were evaluated at aggregate levels. Detection (presence/absence) and quantification (viral load) of SARS-CoV-2 was determined by reverse-transcriptase polymerase chain reaction conducted on floor swabs collected weekly at study locations. The main outcomes, and measures of COVID-19 burden, were (1) weekly regional wastewater signal and (2) weekly admitted COVID-19 patient census from hospitals. We collected 1,863 built environment floor samples over the 6-month study period, with an overall swab positivity for SARS-CoV-2 of 45% (95%CI 43%-48%). We found a strong correlation between overall built environmental swab viral load and hospital COVID-19 census (Spearman’s r = 0.64, p = 0.0017), but no correlation between regional wastewater and hospital COVID-19 census (Spearman’s r = -0.15, p = 0.5). We found a strong correlation (Spearman’s r = 0.76, p = 9x10^-5) between hospital-specific swab viral copy number and hospital-specific COVID-19 census, which is a likely driver of the overall association between swab load and census. Built environment surveillance of SARS-CoV-2 from hospitals was strongly correlated with hospital burden with improved delineation of hospital COVID-19 cases compared to regional wastewater. These findings support the use of built environment surveillance for quantification of infectious burden amongst institutionalized groups.

Built environment surveillance has shown promise for monitoring COVID-19 burden at granular geographic scales, but its utility for surveillance across larger areas and populations is unknown. Our study aims to evaluate the role of built environment detection of SARS-CoV-2 for the surveillance of COVID-19 across broad geographies and populations. We conducted a prospective city-wide sampling study to examine the relationship between SARS-CoV-2 on floors and COVID-19 burden. We used non-parametric correlation analyses and linear models to evaluate associations between SARS-CoV-2 signals and COVID-19 outcomes, across multiple locations/populations over time. Sampling sites included schools, libraries, and emergency departments in the capital city of Ottawa, Canada, from October 2022 to March 2023. Floor sampling was performed across spaces, and outcomes were evaluated at aggregate levels. Detection (presence/absence) and quantification (viral load) of SARS-CoV-2 was determined by reverse-transcriptase polymerase chain reaction conducted on floor swabs collected weekly at study locations. The main outcomes, and measures of COVID-19 burden, were (1) weekly regional wastewater signal and (2) weekly admitted COVID-19 patient census from hospitals. We collected 1,863 built environment floor samples over the 6-month study period, with an overall swab positivity for SARS-CoV-2 of 45% (95%CI 43%-48%). We found a strong correlation between overall built environmental swab viral load and hospital COVID-19 census (Spearman’s r =0.64, p =0.0017), but no correlation between regional wastewater and hospital COVID-19 census (Spearman’s r =-0.15, p=0.5). We found a strong correlation (Spearman’s r =0.76, p =9x10 ^-5 ) between hospital-specific swab viral copy number and hospital-specific COVID-19 census, which is a likely driver of the overall association between swab load and census. Built environment surveillance of SARS-CoV-2 from hospitals was strongly correlated with hospital burden with improved delineation of hospital COVID-19 cases compared to regional wastewater. These findings support the use of built environment surveillance for quantification of infectious burden amongst institutionalized groups.

Introduction Economic evaluations of HIV pre-exposure prophylaxis (PrEP) and associated implementation strategies guide evidence-based policies, programmes, and resource allocation. Since 2015, there has been an evolution in PrEP modalities, implementation strategies, and prioritization of key populations with unmet HIV prevention needs, alongside the scale-up of other HIV prevention interventions. Our systematic review describes the evolving landscape of economic evaluations of PrEP to help identify evidence gaps relevant to the current HIV epidemic and response (PROSPERO: CRD42016038440). Methods We searched five databases, without language restrictions, for peer-reviewed economic evaluations from inception to December 23, 2021. We describe the evolution of study characteristics over time, including perspective of analysis, region, population, PrEP modality/implementation strategy, and comparators. Results Of 3877 studies identified, 87 met inclusion criteria, of which 58 examined HIV epidemics in 2015 or later and 15 adopted a societal perspective. HIV epidemics studied primarily spanned countries in Sub-Saharan Africa (N=34) and in North America (N=25). Modeled populations for receipt of PrEP primarily comprised: gay, bisexual, and other men who have sex with men (N=47), sex workers (N=15), serodifferent partnerships (N=14), and persons who inject drugs (N=10). Most evaluated oral, daily PrEP (N=50), followed by oral, on-demand PrEP (N=9), long-acting injectable PrEP (N=5), and others (e.g., vaginal ring, topical gel; N=7). Only two studies compared different PrEP modalities with each other. One study evaluated different implementation strategies to increase PrEP uptake, adherence, and persistence. Of the 82 studies that compared PrEP to a combination of other HIV prevention interventions, only 19 scaled up at least part of the comparator over time. Discussion To support decision-making, future economic evaluations should consider costs and benefits beyond the health system and consider comparators that better reflect the current HIV response across regions and populations. The increasing availability of novel PrEP modalities allows future studies to evaluate a mix of PrEP modalities and person-centered implementation strategies. Conclusions The growing number of PrEP economic evaluations have not kept pace with emerging PrEP modalities or the current HIV epidemic/response, resulting in challenges in making evidence-based policies, programmes, and resource allocation.