Population-based evaluation of the effectiveness of nirmatrelvir-ritonavir for reducing hospital admissions and mortality from COVID-19.

BACKGROUND: A randomized controlled trial involving a high-risk, unvaccinated population that was conducted before the Omicron variant emerged found that nirmatrelvir-ritonavir was effective in preventing progression to severe COVID-19. Our objective was to evaluate the effectiveness of nirmatrelvir-ritonavir in preventing severe COVID-19 while Omicron and its subvariants predominate. METHODS: We conducted a population-based cohort study in Ontario that included all residents who were older than 17 years of age and had a positive polymerase chain reaction test for SARS-CoV-2 between Apr. 4 and Aug. 31, 2022. We compared patients treated with nirmatrelvir-ritonavir with patients who were not treated and measured the primary outcome of hospital admission from COVID-19 or all-cause death at 1-30 days, and a secondary outcome of all-cause death. We used weighted logistic regression to calculate weighted odds ratios (ORs) with confidence intervals (CIs) using inverse probability of treatment weighting (IPTW) to control for confounding. RESULTS: The final cohort included 177 545 patients, 8876 (5.0%) who were treated with nirmatrelvir-ritonavir and 168 669 (95.0%) who were not treated. The groups were well balanced with respect to demographic and clinical characteristics after applying stabilized IPTW. We found that the occurrence of hospital admission or death was lower in the group given nirmatrelvir-ritonavir than in those who were not (2.1% v. 3.7%; weighted OR 0.56, 95% CI 0.47-0.67). For death alone, the weighted OR was 0.49 (95% CI 0.39-0.62). Our findings were similar across strata of age, drug-drug interactions, vaccination status and comorbidities. The number needed to treat to prevent 1 case of severe COVID-19 was 62 (95% CI 43-80), which varied across strata. INTERPRETATION: Nirmatrelvir-ritonavir was associated with significantly reduced odds of hospital admission and death from COVID-19, which supports use to treat patients with mild COVID-19 who are at risk for severe disease.

Antibiotic resistance associated with the COVID-19 pandemic: a systematic review and meta-analysis.

BACKGROUND: COVID-19 and antimicrobial resistance (AMR) are two intersecting global public health crises. OBJECTIVE: We aimed to describe the impact of the COVID-19 pandemic on AMR across health care settings. DATA SOURCE: A search was conducted in December 2021 in WHO COVID-19 Research Database with forward citation searching up to June 2022. STUDY ELIGIBILITY: Studies evaluating the impact of COVID-19 on AMR in any population were included and influencing factors were extracted. Reporting of enhanced infection prevention and control and/or antimicrobial stewardship programs was noted. METHODS: Pooling was done separately for Gram-negative and Gram-positive organisms. Random-effects meta-analysis was performed. RESULTS: Of 6036 studies screened, 28 were included and 23 provided sufficient data for meta-analysis. The majority of studies focused on hospital settings (n = 25, 89%). The COVID-19 pandemic was not associated with a change in the incidence density (incidence rate ratio 0.99, 95% CI: 0.67-1.47) or proportion (risk ratio 0.91, 95% CI: 0.55-1.49) of methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci cases. A non-statistically significant increase was noted for resistant Gram-negative organisms (i.e. extended-spectrum beta-lactamase, carbapenem-resistant Enterobacterales, carbapenem or multi-drug resistant or carbapenem-resistant Pseudomonas aeruginosa or Acinetobacter baumannii, incidence rate ratio 1.64, 95% CI: 0.92-2.92; risk ratio 1.08, 95% CI: 0.91-1.29). The absence of reported enhanced infection prevention and control and/or antimicrobial stewardship programs initiatives was associated with an increase in gram-negative AMR (risk ratio 1.11, 95% CI: 1.03-1.20). However, a test for subgroup differences showed no statistically significant difference between the presence and absence of these initiatives (p 0.40). CONCLUSION: The COVID-19 pandemic may have hastened the emergence and transmission of AMR, particularly for Gram-negative organisms in hospital settings. But there is considerable heterogeneity in both the AMR metrics used and the rate of resistance reported across studies. These findings reinforce the need for strengthened infection prevention, antimicrobial stewardship, and AMR surveillance in the context of the COVID-19 pandemic.

A cross-sectional study of hospital antimicrobial stewardship programmes in the COVID-19 era.

Background: Antimicrobial resistance (AMR) continues to be a global public health issue amid the COVID-19 pandemic; however, unprecedented demands on hospital antimicrobial stewardship programmes (ASPs) potentially altered their core activities. Objective: We sought to understand how ASPs have been involved in and impacted by the pandemic. Methods: The 2021 Ontario ASP Landscape Survey was developed based on previous provincial questionnaires and emerging literature on the impact of COVID-19 on hospital ASPs. After pre-testing and piloting, the online questionnaire was distributed to hospital antimicrobial stewardship practitioners in the fall of 2021. Descriptive statistics and inductive thematic analysis were performed. Results: The response rate was 78% (98/125 organizations); 96% (94/98) of organizations had or were in the process of formalizing an ASP and 53% (50/94) reported designated funding/resources. Despite 82% reporting no change in dedicated full-time equivalents during the pandemic, ASPs were frequently involved in developing treatment guidelines/clinical pathways (51%), anticipating/managing drug shortages (46%) and obtaining investigational use drugs (32%). While many core ASP activities continued, prospective audit and feedback and prescriber education were modified or suspended by 43% and 40% of programmes, respectively. Decreased frequency, adaptation of activities (i.e. virtual or other technology) and challenges with staffing/resources were commonly reported themes. Knowledge translation (KT) activities and 'collaboration and coordination' also emerged as salient themes. Conclusions: Hospital antimicrobial stewardship practitioners in Ontario have made significant contributions to the pandemic response while continuing to deliver adapted ASP services, despite resource constraints. Moving forward, ASPs will need to continue building capacity while leveraging broader networks to advance the antimicrobial stewardship agenda.

Antimicrobial resistance in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Frequent use of antibiotics in patients with COVID-19 threatens to exacerbate antimicrobial resistance. We aimed to establish the prevalence and predictors of bacterial infections and antimicrobial resistance in patients with COVID-19. METHODS: We did a systematic review and meta-analysis of studies of bacterial co-infections (identified within ≤48 h of presentation) and secondary infections (>48 h after presentation) in outpatients or hospitalised patients with COVID-19. We searched the WHO COVID-19 Research Database to identify cohort studies, case series, case-control trials, and randomised controlled trials with populations of at least 50 patients published in any language between Jan 1, 2019, and Dec 1, 2021. Reviews, editorials, letters, pre-prints, and conference proceedings were excluded, as were studies in which bacterial infection was not microbiologically confirmed (or confirmed via nasopharyngeal swab only). We screened titles and abstracts of papers identified by our search, and then assessed the full text of potentially relevant articles. We reported the pooled prevalence of bacterial infections and antimicrobial resistance by doing a random-effects meta-analysis and meta-regression. Our primary outcomes were the prevalence of bacterial co-infection and secondary infection, and the prevalence of antibiotic-resistant pathogens among patients with laboratory-confirmed COVID-19 and bacterial infections. The study protocol was registered with PROSPERO (CRD42021297344). FINDINGS: We included 148 studies of 362 976 patients, which were done between December, 2019, and May, 2021. The prevalence of bacterial co-infection was 5·3% (95% CI 3·8-7·4), whereas the prevalence of secondary bacterial infection was 18·4% (14·0-23·7). 42 (28%) studies included comprehensive data for the prevalence of antimicrobial resistance among bacterial infections. Among people with bacterial infections, the proportion of infections that were resistant to antimicrobials was 60·8% (95% CI 38·6-79·3), and the proportion of isolates that were resistant was 37·5% (26·9-49·5). Heterogeneity in the reported prevalence of antimicrobial resistance in organisms was substantial (I2=95%). INTERPRETATION: Although infrequently assessed, antimicrobial resistance is highly prevalent in patients with COVID-19 and bacterial infections. Future research and surveillance assessing the effect of COVID-19 on antimicrobial resistance at the patient and population level are urgently needed. FUNDING: WHO.

Ten ways to make the most of World Antimicrobial Awareness Week.

One fundamental strategy to address the public health threat of antimicrobial resistance (AMR) is improved awareness among the public, prescribers, and policy makers with the aim of engaging these groups to act. World Antimicrobial Awareness Week is an opportunity for concerted and consistent communication regarding practical strategies to prevent and mitigate AMR. We highlight 10 ways for antimicrobial stewards to make the most of World Antimicrobial Awareness Week.

Go V.I.R.A.L.: Social Media Engagement Strategies in Infectious Diseases.

Social media has emerged as a tool to facilitate communication and dissemination of information for both patients and healthcare professionals. We describe 3 social media engagement strategies used to reach a broad and diverse audience on the topics of infectious diseases and antimicrobial stewardship, including the use of memes, a clue-based knowledge assessment quiz, and a personality quiz. We describe a novel acronym "VIRAL" to guide engaging social media strategies in healthcare, including eye catching Visuals, Interactive content, showing Respect and empathy for the audience, Adapting to new technology, and making Learning fun.

Global resilience and new strategies needed for antimicrobial stewardship during the COVID-19 pandemic and beyond.

Resilience is having the ability to respond to adversity proactively and resourcefully. The coronavirus disease 2019 (COVID-19) pandemic's profound impact on antimicrobial stewardship programs (ASP) requires clinicians to call on their own resilience to manage the demands of the pandemic and the disruption of ASP activities. This article provides examples of ASP resilience from pharmacists and physicians from seven countries with different resources and approaches to ASP-The United States, The United Kingdom, Canada, Nigeria, Lebanon, South Africa, and Colombia. The lessons learned pertain to providing ASP clinical services in the context of a global pandemic, developing new ASP paradigms in the face of COVID-19, leveraging technology to extend the reach of ASP, and conducting international collaborative ASP research remotely. This article serves as an example of how resilience and global collaboration is sustaining our ASPs by sharing new "how to" do antimicrobial stewardship practices during the COVID-19 pandemic.

Pharmacokinetic/Pharmacodynamic Considerations of Alternate Dosing Strategies of Tocilizumab in COVID-19.

Tocilizumab is one of few treatments that have been shown to improve mortality in patients with coronavirus disease 2019 (COVID-19), but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters that likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the US FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, although weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/pharmacodynamic insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.

Predictors and microbiology of respiratory and bloodstream bacterial infection in patients with COVID-19: living rapid review update and meta-regression.

BACKGROUND: The prevalence of bacterial infection in patients with COVID-19 is low, however, empiric antibiotic use is high. Risk stratification may be needed to minimize unnecessary empiric antibiotic use. OBJECTIVE: To identify risk factors and microbiology associated with respiratory and bloodstream bacterial infection in patients with COVID-19. DATA SOURCES: We searched MEDLINE, OVID Epub and EMBASE for published literature up to 5 February 2021. STUDY ELIGIBILITY CRITERIA: Studies including at least 50 patients with COVID-19 in any healthcare setting. METHODS: We used a validated ten-item risk of bias tool for disease prevalence. The main outcome of interest was the proportion of COVID-19 patients with bloodstream and/or respiratory bacterial co-infection and secondary infection. We performed meta-regression to identify study population factors associated with bacterial infection including healthcare setting, age, comorbidities and COVID-19 medication. RESULTS: Out of 33 345 studies screened, 171 were included in the final analysis. Bacterial infection data were available from 171 262 patients. The prevalence of co-infection was 5.1% (95% CI 3.6-7.1%) and secondary infection was 13.1% (95% CI 9.8-17.2%). There was a higher odds of bacterial infection in studies with a higher proportion of patients in the intensive care unit (ICU) (adjusted OR 18.8, 95% CI 6.5-54.8). Female sex was associated with a lower odds of secondary infection (adjusted OR 0.73, 95% CI 0.55-0.97) but not co-infection (adjusted OR 1.05, 95% CI 0.80-1.37). The most common organisms isolated included Staphylococcus aureus, coagulase-negative staphylococci and Klebsiella species. CONCLUSIONS: While the odds of respiratory and bloodstream bacterial infection are low in patients with COVID-19, meta-regression revealed potential risk factors for infection, including ICU setting and mechanical ventilation. The risk for secondary infection is substantially greater than the risk for co-infection in patients with COVID-19. Understanding predictors of co-infection and secondary infection may help to support improved antibiotic stewardship in patients with COVID-19.

The Impact of COVID-19 on Outpatient Antibiotic Prescriptions in Ontario, Canada; An Interrupted Time Series Analysis.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has potentially impacted outpatient antibiotic prescribing. Investigating this impact may identify stewardship opportunities in the ongoing COVID-19 period and beyond. METHODS: We conducted an interrupted time series analysis on outpatient antibiotic prescriptions and antibiotic prescriptions/patient visits in Ontario, Canada, between January 2017 and December 2020 to evaluate the impact of the COVID-19 pandemic on population-level antibiotic prescribing by prescriber specialty, patient demographics, and conditions. RESULTS: In the evaluated COVID-19 period (March-December 2020), there was a 31.2% (95% CI, 27.0% to 35.1%) relative reduction in total antibiotic prescriptions. Total outpatient antibiotic prescriptions decreased during the COVID-19 period by 37.1% (95% CI, 32.5% to 41.3%) among family physicians, 30.7% (95% CI, 25.8% to 35.2%) among subspecialist physicians, 12.1% (95% CI, 4.4% to 19.2%) among dentists, and 25.7% (95% CI, 21.4% to 29.8%) among other prescribers. Antibiotics indicated for respiratory infections decreased by 43.7% (95% CI, 38.4% to 48.6%). Total patient visits and visits for respiratory infections decreased by 10.7% (95% CI, 5.4% to 15.6%) and 49.9% (95% CI, 43.1% to 55.9%). Total antibiotic prescriptions/1000 visits decreased by 27.5% (95% CI, 21.5% to 33.0%), while antibiotics indicated for respiratory infections/1000 visits with respiratory infections only decreased by 6.8% (95% CI, 2.7% to 10.8%). CONCLUSIONS: The reduction in outpatient antibiotic prescribing during the COVID-19 pandemic was driven by less antibiotic prescribing for respiratory indications and largely explained by decreased visits for respiratory infections.

Antibiotic prescribing in patients with COVID-19: rapid review and meta-analysis.

BACKGROUND: The proportion of patients infected with SARS-CoV-2 that are prescribed antibiotics is uncertain, and may contribute to patient harm and global antibiotic resistance. OBJECTIVE: The aim was to estimate the prevalence and associated factors of antibiotic prescribing in patients with COVID-19. DATA SOURCES: We searched MEDLINE, OVID Epub and EMBASE for published literature on human subjects in English up to June 9 2020. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials; cohort studies; case series with ≥10 patients; and experimental or observational design that evaluated antibiotic prescribing. PARTICIPANTS: The study participants were patients with laboratory-confirmed SARS-CoV-2 infection, across all healthcare settings (hospital and community) and age groups (paediatric and adult). METHODS: The main outcome of interest was proportion of COVID-19 patients prescribed an antibiotic, stratified by geographical region, severity of illness and age. We pooled proportion data using random effects meta-analysis. RESULTS: We screened 7469 studies, from which 154 were included in the final analysis. Antibiotic data were available from 30 623 patients. The prevalence of antibiotic prescribing was 74.6% (95% CI 68.3-80.0%). On univariable meta-regression, antibiotic prescribing was lower in children (prescribing prevalence odds ratio (OR) 0.10, 95% CI 0.03-0.33) compared with adults. Antibiotic prescribing was higher with increasing patient age (OR 1.45 per 10 year increase, 95% CI 1.18-1.77) and higher with increasing proportion of patients requiring mechanical ventilation (OR 1.33 per 10% increase, 95% CI 1.15-1.54). Estimated bacterial co-infection was 8.6% (95% CI 4.7-15.2%) from 31 studies. CONCLUSIONS: Three-quarters of patients with COVID-19 receive antibiotics, prescribing is significantly higher than the estimated prevalence of bacterial co-infection. Unnecessary antibiotic use is likely to be high in patients with COVID-19.

Global contributions of pharmacists during the COVID-19 pandemic.

Throughout the SARS-CoV-2 (COVID-19) global pandemic, pharmacists were rarely mentioned as essential frontline health care providers by the news media, the public, or politicians. Around the world, pharmacists are working on the frontlines of health care every day providing essential health care services during the pandemic. Pharmacists are medication experts providing patient care in a variety of settings including hospitals, clinics, community pharmacies, long-term care, physician offices, and national and public health. In this paper, we describe how pharmacists from high and low-middle income countries contributed to essential patient care and well-being of the public during the COVID-19 pandemic. While the news media, the public, and politicians often overlooked pharmacists as essential frontline health care providers, we hope that this list of contributions by pharmacists from nine countries in this article can help to change this perspective.

Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis.

BACKGROUND: Bacterial co-pathogens are commonly identified in viral respiratory infections and are important causes of morbidity and mortality. The prevalence of bacterial infection in patients infected with SARS-CoV-2 is not well understood. AIMS: To determine the prevalence of bacterial co-infection (at presentation) and secondary infection (after presentation) in patients with COVID-19. SOURCES: We performed a systematic search of MEDLINE, OVID Epub and EMBASE databases for English language literature from 2019 to April 16, 2020. Studies were included if they (a) evaluated patients with confirmed COVID-19 and (b) reported the prevalence of acute bacterial infection. CONTENT: Data were extracted by a single reviewer and cross-checked by a second reviewer. The main outcome was the proportion of COVID-19 patients with an acute bacterial infection. Any bacteria detected from non-respiratory-tract or non-bloodstream sources were excluded. Of 1308 studies screened, 24 were eligible and included in the rapid review representing 3338 patients with COVID-19 evaluated for acute bacterial infection. In the meta-analysis, bacterial co-infection (estimated on presentation) was identified in 3.5% of patients (95%CI 0.4-6.7%) and secondary bacterial infection in 14.3% of patients (95%CI 9.6-18.9%). The overall proportion of COVID-19 patients with bacterial infection was 6.9% (95%CI 4.3-9.5%). Bacterial infection was more common in critically ill patients (8.1%, 95%CI 2.3-13.8%). The majority of patients with COVID-19 received antibiotics (71.9%, 95%CI 56.1 to 87.7%). IMPLICATIONS: Bacterial co-infection is relatively infrequent in hospitalized patients with COVID-19. The majority of these patients may not require empirical antibacterial treatment.