Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial.

BACKGROUND: To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. METHODS: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 µg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. FINDINGS: Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15-16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49-31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. INTERPRETATION: Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. FUNDING: The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

Development and evaluation of a primary care antimicrobial stewardship program (PC-ASP) in Toronto, Ontario, Canada.

Background: Effective community-based antimicrobial stewardship programs (ASPs) are needed because 90% of antimicrobials are prescribed in the community. A primary care ASP (PC-ASP) was evaluated for its effectiveness in lowering antibiotic prescriptions for six common infections. Methods: A multi-faceted educational program was assessed using a before-and-after design in four primary care clinics from 2015 through 2017. The primary outcome was the difference between control and intervention clinics in total antibiotic prescriptions for six common infections before and after the intervention. Secondary outcomes included changes in condition-specific antibiotic use, delayed antibiotic prescriptions, prescriptions exceeding 7 days duration, use of recommended antibiotics, and emergency department visits or hospitalizations within 30 days. Multi-method models adjusting for demographics, case mix, and clustering by physician were used to estimate treatment effects. Results: Total antibiotic prescriptions in control and intervention clinics did not differ (difference in differences = 1.7%; 95% CI -12.5% to 15.9%), nor did use of delayed prescriptions (-5.2%; 95% CI -24.2% to 13.8%). Prescriptions for longer than 7 days were significantly reduced (-21.3%; 95% CI -42.5% to -0.1%). However, only 781 of 1,777 encounters (44.0%) involved providers who completed the ASP education. Where providers completed the education, delayed prescriptions increased 17.7% (p = 0.06), and prescriptions exceeding 7 days duration declined (-27%; 95% CI -48.3% to -5.6%). Subsequent emergency department visits and hospitalizations did not increase. Conclusions: PC-ASP effectiveness on antibiotic use was variable. Shorter prescription durations and increased use of delayed prescriptions were adopted by engaged primary care providers.

Historique: Des programmes de gestion antimicrobienne (PGA) communautaires efficaces doivent exister, parce que 90 % des antimicrobiens sont prescrits dans la communauté. Des chercheurs ont évalué un PGA en première ligne (PGA-PL) afin d'en déterminer l'efficacité à réduire les prescriptions d'antibiotiques pour six infections courantes. Méthodologie: Les chercheurs ont évalué un programme de formation polyvalent au moyen d'une méthodologie avant-après dans quatre cliniques de soins de première ligne entre 2015 et 2017. Le résultat clinique primaire était la différence entre les cliniques de contrôle et d'intervention pour ce qui est du total de prescriptions antibiotiques contre six infections courantes avant et après l'intervention. Les résultats cliniques secondaires incluaient des modifications à l'utilisation des antibiotiques propres au trouble de santé, le report des prescriptions d'antibiotiques, des prescriptions de plus de sept jours, l'utilisation des antibiotiques recommandés et les visites à l'urgence ou les hospitalisations dans les 30 jours. Les chercheurs ont utilisé des méthodes multimodèles tenant compte de la démographie, du mélange de cas et du regroupement par médecin pour évaluer l'effet des traitements. Résultats: Les prescriptions totales d'antibiotiques dans les cliniques de contrôle et d'intervention ne différaient pas (différences des différences = 1,7 %; IC à 95 %, ­12,5 % à 15,9 %), ni l'utilisation de prescriptions reportées (­5,2 %; IC à 95 %, ­24,2 % à 13,8 %). Les prescriptions de plus de sept jours étaient très peu courantes (­21,3 %; IC à 95 %, ­42,5 % à ­0,1 %). Cependant, seulement 781 des 1 777 rencontres (44,0 %) avaient eu lieu avec des dispensateurs qui avaient suivi la formation sur le PGA. Lorsque les dispensateurs avaient suivi la formation, les reports de prescriptions augmentaient de 17,7 % (p = 0,06) et les prescriptions de plus de sept jours diminuaient (­27 %; IC à 95 %, ­48,3 % à ­5,6 %). Les visites subséquentes à l'urgence et les hospitalisations n'ont pas augmenté. Conclusions: L'efficacité du PGA-PL pour l'utilisation d'antibiotiques était variable. Les dispensateurs de soins de première ligne qui y avaient participé préparaient des prescriptions de moins longue durée et reportaient davantage leurs prescriptions.

The evolving epidemiology of Clostridium difficile infection in Canadian hospitals during a postepidemic period (2009-2015).

BACKGROUND: The clinical and molecular epidemiology of health care-associated Clostridium difficile infection in nonepidemic settings across Canada has evolved since the first report of the virulent North American pulsed-field gel electrophoresis type 1 (NAP1) strain more than 15 years ago. The objective of this national, multicentre study was to describe the evolving epidemiology and molecular characteristics of health care-associated C. difficile infection in Canada during a post-NAP1-epidemic period, particularly patient outcomes associated with the NAP1 strain. METHODS: Adult inpatients with C. difficile infection were prospectively identified, using a standard definition, between 2009 and 2015 through the Canadian Nosocomial Infection Surveillance Program (CNISP), a network of 64 acute care hospitals. Patient demographic characteristics, severity of infection and outcomes were reviewed. Molecular testing was performed on isolates, and strain types were analyzed against outcomes and epidemiologic trends. RESULTS: Over a 7-year period, 20 623 adult patients admitted to hospital with health care-associated C. difficile infection were reported to CNISP, and microbiological data were available for 2690 patients. From 2009 to 2015, the national rate of health care-associated C. difficile infection decreased from 5.9 to 4.3 per 10 000 patient-days. NAP1 remained the dominant strain type, but infection with this strain has significantly decreased over time, followed by an increasing trend of infection with NAP4 and NAP11 strains. The NAP1 strain was significantly associated with a higher rate of death attributable to C. difficile infection compared with non-NAP1 strains (odds ratio 1.91, 95% confidence interval [CI] 1.29-2.82). Isolates were universally susceptible to metronidazole; one was nonsusceptible to vancomycin. The proportion of NAP1 strains within individual centres predicted their rates of health care-associated C. difficile infection; for every 10% increase in the proportion of NAP1 strains, the rate of health care-associated C. difficile infection increased by 3.3% (95% CI 1.7%-4.9%). INTERPRETATION: Rates of health care-associated C. difficile infection have decreased across Canada. In nonepidemic settings, NAP4 has emerged as a common strain type, but NAP1, although decreasing, continues to be the predominant circulating strain and remains significantly associated with higher attributable mortality.

Key Advantages of a Targeted Incident Reporting System for Severe and Critical Clostridium difficile Infection Incidents.

There is little guidance on how to design and implement an incident reporting system (IRS) targeted at one of the most common types of adverse events in hospitals: hospital-associated infections. In this article, we describe an IRS for severe and critical Clostridium difficile infection incidents and highlight its key advantages.

Influenza Vaccination of Healthcare Workers: Critical Analysis of the Evidence for Patient Benefit Underpinning Policies of Enforcement.

BACKGROUND: Four cluster randomized controlled trials (cRCTs) conducted in long-term care facilities (LTCFs) have reported reductions in patient risk through increased healthcare worker (HCW) influenza vaccination. This evidence has led to expansive policies of enforcement that include all staff of acute care hospitals and other healthcare settings beyond LTCFs. We critique and quantify the cRCT evidence for indirect patient benefit underpinning policies of mandatory HCW influenza vaccination. METHODS: Plausibility of the four cRCT findings attributing indirect patient benefits to HCW influenza vaccination was assessed by comparing percentage reductions in patient risk reported by the cRCTs to predicted values. Plausibly predicted values were derived according to the basic mathematical principle of dilution, taking into account HCW influenza vaccine coverage and the specificity of patient outcomes for influenza. Accordingly, predicted values were calculated as a function of relevant compound probabilities including vaccine efficacy (ranging 40-60% in HCWs and favourably assuming the same indirect protection conferred through them to patients) × change in proportionate HCW influenza vaccine coverage (as reported by each cRCT) × percentage of a given patient outcome (e.g. influenza-like illness (ILI) or all-cause mortality) plausibly due to influenza virus. The number needed to vaccinate (NNV) for HCWs to indirectly prevent patient death was recalibrated based on real patient data of hospital-acquired influenza, with adjustment for potential under-detection (5.2-fold), and using favourable assumptions of HCW-attributable risk (ranging 60-80%). RESULTS: In attributing patient benefit to increased HCW influenza vaccine coverage, each cRCT was found to violate the basic mathematical principle of dilution by reporting greater percentage reductions with less influenza-specific patient outcomes (i.e., all-cause mortality > ILI > laboratory-confirmed influenza) and/or patient mortality reductions exceeding even favourably-derived predicted values by at least 6- to 15-fold. If extrapolated to all LTCF and hospital staff in the United States, the prior cRCT-claimed NNV of 8 would implausibly mean >200,000 and >675,000 patient deaths, respectively, could be prevented annually by HCW influenza vaccination, inconceivably exceeding total US population mortality estimates due to seasonal influenza each year, or during the 1918 pandemic, respectively. More realistic recalibration based on actual patient data instead shows that at least 6000 to 32,000 hospital workers would need to be vaccinated before a single patient death could potentially be averted. CONCLUSIONS: The four cRCTs underpinning policies of enforced HCW influenza vaccination attribute implausibly large reductions in patient risk to HCW vaccination, casting serious doubts on their validity. The impression that unvaccinated HCWs place their patients at great influenza peril is exaggerated. Instead, the HCW-attributable risk and vaccine-preventable fraction both remain unknown and the NNV to achieve patient benefit still requires better understanding. Although current scientific data are inadequate to support the ethical implementation of enforced HCW influenza vaccination, they do not refute approaches to support voluntary vaccination or other more broadly protective practices, such as staying home or masking when acutely ill.

Periprosthetic Infection following Primary Hip and Knee Arthroplasty: The Impact of Limiting the Postoperative Surveillance Period.

BACKGROUND Hip and knee arthroplasty infections are associated with considerable healthcare costs. The merits of reducing the postoperative surveillance period from 1 year to 90 days have been debated. OBJECTIVES To report the first pan-Canadian hip and knee periprosthetic joint infection (PJI) rates and to describe the implications of a shorter (90-day) postoperative surveillance period. METHODS Prospective surveillance for infection following hip and knee arthroplasty was conducted by hospitals participating in the Canadian Nosocomial Infection Surveillance Program (CNISP) using standard surveillance definitions. RESULTS Overall hip and knee PJI rates were 1.64 and 1.52 per 100 procedures, respectively. Deep incisional and organ-space hip and knee PJI rates were 0.96 and 0.71, respectively. In total, 93% of hip PJIs and 92% of knee PJIs were identified within 90 days, with a median time to detection of 21 days. However, 11%-16% of deep incisional and organ-space infections were not detected within 90 days. This rate was reduced to 3%-4% at 180 days post procedure. Anaerobic and polymicrobial infections had the shortest median time from procedure to detection (17 and 18 days, respectively) compared with infections due to other microorganisms, including Staphylococcus aureus. CONCLUSIONS PJI rates were similar to those reported elsewhere, although differences in national surveillance systems limit direct comparisons. Our results suggest that a postoperative surveillance period of 90 days will detect the majority of PJIs; however, up to 16% of deep incisional and organ-space infections may be missed. Extending the surveillance period to 180 days could allow for a better estimate of disease burden. Infect Control Hosp Epidemiol 2017;38:147-153.

Longitudinal Multicenter Analysis of Outcomes After Cessation of Control Measures for Vancomycin-Resistant Enterococci.

OBJECTIVE To assess clinically relevant outcomes after complete cessation of control measures for vancomycin-resistant enterococci (VRE). DESIGN Quasi-experimental ecological study over 3.5 years. METHODS All VRE screening and isolation practices at 4 large academic hospitals in Ontario, Canada, were stopped on July 1, 2012. In total, 618 anonymized abstracted charts of patients with VRE-positive clinical isolates identified between July 1, 2010, and December 31, 2013, were reviewed to determine whether the case was a true VRE infection, a VRE colonization or contaminant, or a true VRE bacteremia. All deaths within 30 days of the last VRE infection were also reviewed to determine whether the death was fully or partially attributable to VRE. All-cause mortality was evaluated over the study period. Generalized estimating equation methods were used to cluster outcome rates within hospitals, and negative binomial models were created for each outcome. RESULTS The incidence rate ratio (IRR) for VRE infections was 0.59 and the associated P value was .34. For VRE bacteremias, the IRR was 0.54 and P=.38; for all-cause mortality the IRR was 0.70 and P=.66; and for VRE attributable death, the IRR was 0.35 and P=.49. VRE control measures were not significantly associated with any of the outcomes. Rates of all outcomes appeared to increase during the 18-month period after cessation of VRE control measures, but none reached statistical significance. CONCLUSION Clinically significant VRE outcomes remain rare. Cessation of all control measures for VRE had no significant attributable adverse clinical impact. Infect Control Hosp Epidemiol 2016;1-7.

Healthcare-associated infections as patient safety indicators.

Healthcare-associated infections (HAIs) are a pressing and imminent patient safety concern as they cause substantial preventable morbidity and mortality. Despite this, there is a strong tendency for healthcare administrators and providers to view them as far less of a threat to patient safety than adverse events such as medication administration errors and falls. Further, validated strategies to prevent HAIs are frequently slow to be adopted. This paper reviews two HAIs of increasing visibility and importance - namely, methicillin-resistant Staphylococcus aureus and Clostridium difficile - and discusses the pivotal importance of hand hygiene and environmental cleaning in their prevention. Possible reasons why HAIs are approached differently from other patient safety issues are discussed, including the false sense of security created by the advent of antibiotics, the lack of randomized controlled trials supporting infection-control interventions and the systemic multifactorial causes of HAIs that result in a need for interventions that go far beyond traditional clinical boundaries. Suggested strategies to improve patient safety with respect to HAIs are provided, including a focus on the role of potential links to accreditation; the role of public reporting; healthcare facility design; change management strategies; visible leadership and role modelling; collaboration between facilities and with public health; reducing hospital overcrowding; and accountability and funding. Finally, the impact of the burgeoning interest of the media, the threat of legal liability and the well-being of healthcare providers are discussed.

Outbreak of multidrug-resistant Pseudomonas aeruginosa colonization and infection secondary to imperfect intensive care unit room design.

BACKGROUND: Pseudomonas aeruginosa has been increasingly recognized for its ability to cause significant hospital-associated outbreaks, particularly since the emergence of multidrug-resistant strains. Biofilm formation allows the pathogen to persist in environmental reservoirs. Thus, multiple hospital room design elements, including sink placement and design, can impact nosocomial transmission of P. aeruginosa and other pathogens. METHODS: From December 2004 through March 2006, 36 patients exposed to the intensive care unit or transplant units of a tertiary care hospital were infected with a multidrug-resistant strain of P. aeruginosa. All phenotypically similar isolates were examined for genetic relatedness by means of pulsed-field gel electrophoresis. Clinical characteristics of the affected patients were collected, and a detailed epidemiological and environmental investigation of potential sources was carried out. RESULTS: Seventeen of the infected patients died within 3 months; for 12 (71%) of these patients, infection with the outbreak organism contributed to or directly caused death. The source of the outbreak was traced to hand hygiene sink drains, where biofilms containing viable organisms were found. Testing by use of a commercial fluorescent marker demonstrated that when the sink was used for handwashing, drain contents splashed at least 1 meter from the sink. Various attempts were made to disinfect the drains, but it was only when the sinks were renovated to prevent splashing onto surrounding areas that the outbreak was terminated. CONCLUSION: This report highlights the importance of biofilms and of sink and patient room design in the propagation of an outbreak and suggests some strategies to reduce the risks associated with hospital sinks.

Transmission of influenza A in human beings.

Planning for the next influenza pandemic is occurring at many levels throughout the world, spurred on by the recent spread of H5N1 avian influenza in Asia, Europe, and Africa. Central to these planning efforts in the health-care sector are strategies to minimise the transmission of influenza to health-care workers and patients. The infection control precautions necessary to prevent airborne, droplet, and contact transmission are quite different and will need to be decided on and planned before a pandemic occurs. Despite vast clinical experience in human beings, there continues to be much debate about how influenza is transmitted. We have done a systematic review of the English language experimental and epidemiological literature on this subject to better inform infection control planning efforts. We have found that the existing data are limited with respect to the identification of specific modes of transmission in the natural setting. However, we are able to conclude that transmission occurs at close range rather than over long distances, suggesting that airborne transmission, as traditionally defined, is unlikely to be of significance in most clinical settings. Further research is required to better define conditions under which the influenza virus may transmit via the airborne route.