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Background The health impact of antimicrobial resistance (AMR) has not been included in the Global Burden of Disease (GBD) report, as reliable data have been lacking. AMR burden estimates have been derived from models combining incidence and/or prevalence data from national and/or international surveillance systems and mortality estimates from clinical studies. Depending on utilized empirical data, statistical methodology and applied endpoints, the validity and reliability of results can differ substantially. Objectives We assessed comprehensiveness, and internal and external validity of studies estimating the clinical impact of infections caused by the priority antibiotic resistant pathogens monitored by the WHO Global Antimicrobial Resistance Surveillance System. Data sources Ovid MEDLINE, January 1950 to March 2019, In-Process and other non-indexed citations were searched. Study eligibility criteria Studies reporting mortality, length of hospital stay, duration of the disease until remission and/or death, complications, hospital re-admissions, and follow-up beyond hospital discharge were eligible. Methods The literature was searched according to the Cochrane recommendations and reported according to Preferred Reporting Items for Systematic Reviews. Results Two-hundred and eighty-six studies out of 3529 were eligible. Studies derived mainly from high-income countries (215, 75%) and relied on data from retrospective (226, 79%), single-centre (201, 70%), cohort studies (243, 85%). The health impact was mostly limited to all-cause mortality (128, 45%) with heterogeneity in timing of assessment; attributable length of hospital stay was seldom adjusted for pre-infection admission time and a few studies had enough follow-up for assessing long-term sequelae. Overall, adjustment for confounding has shown a substantial improvement. Data on health state definitions and duration of diseases are generally lacking, precluding calculation of disability-adjusted life years, critical for application of the GBD study methodology. Conclusion Efforts to improve harmonization, representativeness, quality of AMR surveillance data and cohort studies to determine AMR attributable mortality and morbidity are urgently required. Policy makers need accurate and detailed burden estimates to inform prioritization of resource allocation, and to select the most effective intervention strategies to halt the AMR crisis.

Antibiotic stewardship (AS) is a cornerstone of the fight against antimicrobial resistance; however, evidence on the best practice to improve antibiotic prescription in various hospital settings is still scarce. This study aimed to measure the efficacy of a non-restrictive AS intervention in the internal medicine area of a tertiary-care hospital across a 3-year period.The intervention comprised a 3-month 'intensive phase' based on education and guidelines provision, followed by 9 months of audits and feedback activities. The primary outcome was the overall antibiotic consumption measured as days of therapy (DOTs) and defined daily doses (DDDs). Secondary outcomes were carbapenem and fluoroquinolone consumption, all-cause in-hospital mortality, length of stay, incidence of Clostridioides difficile and carbapenem-resistant Enterobacterales bloodstream infections (CRE-BSIs). All outcomes were measured in the intervention wards comparing the pre-phase with the post-phase using an interrupted time-series model.A total of 145 337 patient days (PDs) and 14 159 admissions were included in the analysis. The intervention was associated with reduced DOTs*1000PDs (-162.2/P = 0.005) and DDDs*1000PDs (-183.6/P ≤ 0.001). A sustained decrease in ward-related antibiotic consumption was also detected during the post-intervention phase and in the carbapenem/fluoroquinolone classes. The intervention was associated with an immediate reduction in length of stay (-1.72 days/P0.001) and all-cause mortality (-3.71 deaths*100 admissions/P = 0.002), with a decreasing trend over time. Rates of Clostridioides difficile infections and CRE-BSIs were not significantly impacted by the intervention.The AS intervention was effective and safe in decreasing antibiotic consumption and length of stay in the internal medicine area. Enabling prescribers to judicious use of antimicrobials through active participation in AS initiatives is key to reach sustained results over time.

IMPORTANCE: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. OBJECTIVE: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao(2)/Fio(2)) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. INTERVENTIONS: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. MAIN OUTCOME AND MEASURES: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao(2)/Fio(2) ratio less than 150 mm Hg, whichever came first. RESULTS: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao(2)/Fio(2) ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37